Drug Information

General Information of This Drug
Drug ID DRG00009
Drug Name Camptothecin
Synonyms
camptothecin; 7689-03-4; Camptothecine; (S)-(+)-Camptothecin; Campathecin; (+)-Camptothecine; d-Camptothecin; (+)-Camptothecin; 20(S)-Camptothecine; 21,22-Secocamptothecin-21-oic acid lactone; NSC94600; Camptothecine (S,+); CHEMBL65; (S)-4-ethyl-4-hydroxy-1H-Pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione; NSC-94600; (4S)-4-ethyl-4-hydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione; MLS000766223; XT3Z54Z28A; CHEBI:27656; MFCD00081076; (19S)-19-ethyl-19-hydroxy-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4,6,8,10,15(20)-heptaene-14,18-dione; NSC 100880; (19S)-19-ethyl-19-hydroxy-17-oxa-3,13-diazapentacyclo[11.8.0.0^{2,11}.0^{4,9}.0^{15,20}]henicosa-1(21),2,4(9),5,7,10,15(20)-heptaene-14,18-dione; (S)-Camptothecin; 1H-Pyrano(3',4':6,7)indolizino(1,2-b)quinoline-3,14(4H,12H)-dione, 4-ethyl-4-hydroxy-, (4S)-; 1H-Pyrano(3',4':6,7)indolizino(1,2-b)quinoline-3,14(4H,12H)-dione, 4-ethyl-4-hydroxy-, (S)-; 1H-Pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione, 4-ethyl-4-hydroxy-, (4S)-; 20(S)-Camptothecin; 4-ETHYL-4-HYDROXY-1,12-DIHYDRO-4H-2-OXA-6,12A-DIAZA-DIBENZO[B,H]FLUORENE-3,13-DIONE; SR-01000075798; SR-01000597379; d-camptothecine; (s)-camptothecine; Camptothecin,(S); (4S)-4-ETHYL-4-HYDROXY-1H-PYRANO(3',4':6,7)INDOLIZINO(1,2-B)QUINOLINE-3,14(4H,12H)-DIONE; (S)-4-ethyl-4-hydroxy-1H-Pyrano(3',4':6,7)indolizino(1,2-b)quinoline-3,14(4H,12H)-dione; (S)-4-Ethyl-4-hydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14-(4H,12H)-dione; 1H-Pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione, 4-ethyl-4-hydroxy-, (S)-; Prestwick_102; (+)-Camptothecin;; Camptothecine (8CI); Spectrum_000299; Tocris-1100; SpecPlus_000712; Prestwick0_000200; Prestwick1_000200; Prestwick2_000200; Prestwick3_000200; Spectrum2_000903; Spectrum3_001203; Spectrum4_000738; Spectrum5_001126; CAMPTOTHECIN [MI]; Lopac-C-9911; SCHEMBL6038; UNII-XT3Z54Z28A; Lopac0_000341; BSPBio_000159; BSPBio_002586; KBioGR_001036; KBioSS_000779; KBioSS_002283; cid_24360; CAMPTOTHECIN [WHO-DD]; DivK1c_000826; DivK1c_006808; SPECTRUM1502232; SPBio_000746; SPBio_002080; BPBio1_000175; CCRIS 8162; DTXSID0030956; HMS502J08; KBio1_000826; KBio1_001752; KBio2_000779; KBio2_003347; KBio2_005915; KBio3_002086; 4-Ethyl-4-hydroxy-1H-pyrano-[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione; NINDS_000826; Bio1_000400; Bio1_000889; Bio1_001378; GLXC-10346; HMS1568H21; HMS1921N08; HMS2089F08; HMS2095H21; HMS3261E03; HMS3414J17; HMS3654D13; HMS3678J15; HMS3712H21; BCP02857; Tox21_500341; AC-202; BBL033963; BDBM50008923; CCG-40255; GR-301; NSC 94600; s1288; STK801886; AKOS004119861; CS-1049; DB04690; KS-5235; LP00341; SDCCGMLS-0066688.P001; SDCCGSBI-0050329.P003; BRN 0631069; CAS-2114454; IDI1_000826; NCGC00015290-01; NCGC00016994-01; NCGC00016994-02; NCGC00016994-03; NCGC00016994-04; NCGC00016994-05; NCGC00016994-06; NCGC00016994-07; NCGC00016994-08; NCGC00016994-09; NCGC00016994-10; NCGC00016994-11; NCGC00016994-12; NCGC00016994-16; NCGC00016994-29; NCGC00024997-01; NCGC00024997-02; NCGC00024997-03; NCGC00024997-04; NCGC00024997-05; NCGC00024997-06; NCGC00178592-01; NCGC00178592-02; NCGC00261026-01; 1ST40312; HY-16560; NCI60_042105; SMR000445686; SY010324; AI3-62475; EU-0100341; NS00011856; SW196414-3; C 9911; C01897; M01564; AB00052452-08; AB00052452-09; AB00052452_10; EN300-1725804; (S)-(+)-Camptothecin, >=90% (HPLC), powder; A838882; Q419964; Q-200785; SR-01000075798-1; SR-01000075798-4; SR-01000597379-1; SR-01000597379-3; BRD-K37890730-001-09-4; BRD-K37890730-001-10-2; Z1741982070; (S)-4-ethyl-4-hydroxy-1,12-dihydro-4H-2-oxa-6,12a-diaza-dibenzo[b,h]florene-3,13-dione; (S)-4-ethyl-4-hydroxy-1,12-dihydro-4H-2-oxa-6,12a-diaza-dibenzo[b,h]fluorene-3,13-dione; 4-Ethyl-4-hydroxy-1H-pyrano-[3,4:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione; 4-Ethyl-4-hydroxy-1H-pyrano-[3[,4[:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione; (19S)-19-ethyl-19-hydroxy-17-oxa-3,13-diazapentacyclo[11.8.0.0^{2,11}.0^{4,9}.0^{15,20}]henicosa-1(21),2(11),3,5,7,9,15(20)-heptaene-14,18-dione; (S)-4-Ethyl-4-hydroxy-1H-pyrano-[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione;(S)-(+)-Camptothecin; (S)-4-Ethyl-4-hydroxy-1H-pyrano[3 inverted exclamation mark ,4 inverted exclamation mark :6,7]indolizino[1,2-b]quinoline-3,14-(4H,12H)-dione; 1H-Pyrano[3',7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione, 4-ethyl-4-hydroxy-, (S)-; 4(S)-Ethyl-4-hydroxy-1H-pyrano-[3',4':6,7]indolizino[1,2-b]quinoline-3,14 (4H,12H)-dione; 4-ethyl-4-hydroxy-(4S)-3,4,12,14-tetrahydro-1H-pyrano[3'',4'':6,7]indolizino[1,2-b]quinoline-3,14-dione; 4-Ethyl-4-hydroxy-1,12-dihydro-4H-2-oxa-6,12a-diaza-dibenzo[b,h]fluorene-3,13-dione (camptothecin or CPT); 4-Ethyl-4-hydroxy-1,12-dihydro-4H-2-oxa-6,12a-diaza-dibenzo[b,h]fluorene-3,13-dione (Camptothecin); 4-Ethyl-4-hydroxy-1,12-dihydro-4H-2-oxa-6,12a-diaza-dibenzo[b,h]fluorene-3,13-dione (CPT, Camptothecin)
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Target(s) DNA topoisomerase 1 (TOP1)  Target Info 
Structure
Formula
C20H16N2O4
#Ro5 Violations (Lipinski): 0 Molecular Weight (mw) 348.4
Lipid-water partition coefficient (xlogp) 1
Hydrogen Bond Donor Count (hbonddonor) 1
Hydrogen Bond Acceptor Count (hbondacc) 5
Rotatable Bond Count (rotbonds) 1
PubChem CID
24360
Canonical smiles
CCC1(C2=C(COC1=O)C(=O)N3CC4=CC5=CC=CC=C5N=C4C3=C2)O
InChI
InChI=1S/C20H16N2O4/c1-2-20(25)14-8-16-17-12(7-11-5-3-4-6-15(11)21-17)9-22(16)18(23)13(14)10-26-19(20)24/h3-8,25H,2,9-10H2,1H3/t20-/m0/s1
InChIKey
VSJKWCGYPAHWDS-FQEVSTJZSA-N
IUPAC Name
(19S)-19-ethyl-19-hydroxy-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4,6,8,10,15(20)-heptaene-14,18-dione
The activity data of This Drug
Standard Type Value Administration times Administration dosage Cell line Cell line ID Ref.
Apoptosis rate 55.80% 24 h 2 μM SK-BR-3 cell CVCL_0033 [1]
Cell survival rate 46% 72 h 10 μM B16-F10 cell CVCL_0159 [2]
Cell survival rate 67% 72 h 5 μM B16-F10 cell CVCL_0159 [2]
Cell survival rate 71% 72 h 2.5 μM B16-F10 cell CVCL_0159 [2]
Cell survival rate 82% 72 h 1.25 μM B16-F10 cell CVCL_0159 [2]
Cell survival rate 95% 72 h 0.625 μM B16-F10 cell CVCL_0159 [2]
Tumor Growth Inhibition value (TGI) 39% Injected via tail vein every three days 8 μmol/kg SK-BR-3 cell CVCL_0033 [1]
Half Maximal Inhibitory Concentration (IC50) 0.21±0.03 µM 48 h N.A. HCT 116 cell CVCL_0291 [3]
Half Maximal Inhibitory Concentration (IC50) 0.21±0.04 µM 48 h N.A. SK-BR-3 cell CVCL_0033 [4]
Half Maximal Inhibitory Concentration (IC50) 0.26±0.06 µM 48 h N.A. SK-BR-3 cell CVCL_0033 [1]
Half Maximal Inhibitory Concentration (IC50) 0.38±0.11 µM 48 h N.A. SK-BR-3 cell CVCL_0033 [5]
Half Maximal Inhibitory Concentration (IC50) 0.53±0.21 µM 48 h N.A. MDA-MB-231 cell CVCL_0062 [5]
Half Maximal Inhibitory Concentration (IC50) 0.65±0.03 µM 48 h N.A. SGC-7901 cell CVCL_0520 [3]
Half Maximal Inhibitory Concentration (IC50) 0.68±0.04 µM 48 h N.A. MCF-7 cell CVCL_0031 [3]
Half Maximal Inhibitory Concentration (IC50) 1.06±0.42 µM 48 h N.A. MDA-MB-231 cell CVCL_0062 [4]
Half Maximal Inhibitory Concentration (IC50) 1.12±0.11 µM 48 h N.A. NCM460 cell CVCL_0460 [3]
Half Maximal Inhibitory Concentration (IC50) 2.04±0.20 µM 48 h N.A. GES1 cell CVCL_EQ22 [3]
Half Maximal Inhibitory Concentration (IC50) 2.07±0.67 µM 48 h N.A. NCI-N87 cell CVCL_1603 [5]
Half Maximal Inhibitory Concentration (IC50) 2.07±0.67 µM 48 h N.A. NCI-N87 cell CVCL_1603 [5]
Half Maximal Inhibitory Concentration (IC50) 2.10±1.34 µM 48 h N.A. NCI-N87 cell CVCL_1603 [1]
Half Maximal Inhibitory Concentration (IC50) 2.10±1.34 µM 48 h N.A. NCI-N87 cell CVCL_1603 [1]
Half Maximal Inhibitory Concentration (IC50) 2.32±0.24 µM 48 h N.A. NCI-N87 cell CVCL_1603 [4]
Half Maximal Inhibitory Concentration (IC50) 2.32±0.24 µM 48 h N.A. NCI-N87 cell CVCL_1603 [4]
Half Maximal Inhibitory Concentration (IC50) 2.52±0.22 µM 48 h N.A. LO #2 cell CVCL_C7SD [3]
Half Maximal Inhibitory Concentration (IC50) 2.52±0.22 µM 48 h N.A. LO #2 cell CVCL_C7SD [3]
Half Maximal Inhibitory Concentration (IC50) 2.58±0.77 µM 48 h N.A. MCF-10A cell CVCL_0598 [4]
Half Maximal Inhibitory Concentration (IC50) 3.02±0.49 µM 48 h N.A. MCF-10A cell CVCL_0598 [5]
Half Maximal Inhibitory Concentration (IC50) 3.05±1.24 µM 48 h N.A. MCF-10A cell CVCL_0598 [1]
Half Maximal Inhibitory Concentration (IC50) 3.17±1.15 µM 48 h N.A. MDA-MB-231 cell CVCL_0062 [1]
Half Maximal Inhibitory Concentration (IC50) 3.82±0.91 µM 48 h N.A. SK-OV-3 cell CVCL_0532 [4]
Half Maximal Inhibitory Concentration (IC50) 3.82±0.91 µM 48 h N.A. SK-OV-3 cell CVCL_0532 [4]
Half Maximal Inhibitory Concentration (IC50) 4.07±1.82 µM 48 h N.A. SK-OV-3 cell CVCL_0532 [5]
Half Maximal Inhibitory Concentration (IC50) 4.07±1.82 µM 48 h N.A. SK-OV-3 cell CVCL_0532 [5]
Half Maximal Inhibitory Concentration (IC50) 5.21±0.31 µM 48 h N.A. HCT-116/CPT cell CVCL_0291 [3]
Half Maximal Inhibitory Concentration (IC50) 15.8±0.7 µM 48 h N.A. MCF7/C4 cell CVCL_GX99 [3]
Half Maximal Inhibitory Concentration (IC50) 18.1±1.1 µM 48 h N.A. SGC-7901/CPT cell CVCL_0520 [3]
Half Maximal Cytotoxicity Concentration (CC50) 3 nM N.A. N.A. CCRF-CEM cell CVCL_0207 [6]
Half Maximal Cytotoxicity Concentration (CC50) 4 nM N.A. N.A. MT4 cell CVCL_2632 [6]
Half Maximal Cytotoxicity Concentration (CC50) 5 nM N.A. N.A. WIL2-NS cell CVCL_2761 [7]
Half Maximal Cytotoxicity Concentration (CC50) 6 nM N.A. N.A. KB cell CVCL_0372 [8]
Half Maximal Cytotoxicity Concentration (CC50) 10 nM N.A. N.A. MT4 cell CVCL_2632 [8]
Half Maximal Cytotoxicity Concentration (CC50) 15 nM N.A. N.A. DU145 cell CVCL_0105 [7]
Half Maximal Cytotoxicity Concentration (CC50) 20 nM N.A. N.A. Hep-G2 cell CVCL_0027 [7]
Half Maximal Cytotoxicity Concentration (CC50) 50 nM N.A. N.A. SK-MES-1 cell CVCL_0630 [6]
Half Maximal Cytotoxicity Concentration (CC50) 80 nM N.A. N.A. MCF-7 cell CVCL_0031 [6]
Half Maximal Cytotoxicity Concentration (CC50) 200 nM N.A. N.A. MRC5 cell CVCL_0440 [7]
Half Maximal Effective Concentration (EC50) 10 ng/mL N.A. N.A. KB cell CVCL_0372 [9]
Half Maximal Effective Concentration (EC50) 0.15 nM N.A. N.A. SW620 cell CVCL_0547 [10]
Half Maximal Effective Dosage (ED50) 8.6 pmol/ml N.A. N.A. P388 cell CVCL_7222 [11]
Half Maximal Effective Dosage (ED50) 3.2 nM N.A. N.A. A2780-1A9 cell CVCL_H619 [12]
Half Maximal Effective Dosage (ED50) 3.2 nM N.A. N.A. MCF-7 cell CVCL_0031 [12]
Half Maximal Effective Dosage (ED50) 20.9 nM N.A. N.A. KB cell CVCL_0372 [12]
Half Maximal Effective Dosage (ED50) 57 nM N.A. N.A. Col2 cell CVCL_D645 [13]
Half Maximal Effective Dosage (ED50) >10 uM N.A. N.A. MCF-7 cell CVCL_0031 [14]
Half Maximal Growth Inhibition (GI50) 23 pM N.A. N.A. CCRF-CEM cell CVCL_0207 [15]
Half Maximal Growth Inhibition (GI50) 2 nM N.A. N.A. CCRF-CEM cell CVCL_0207 [16]
Half Maximal Growth Inhibition (GI50) 7 nM N.A. N.A. CCRF-CEM cell CVCL_0207 [17]
Half Maximal Growth Inhibition (GI50) 8 nM N.A. N.A. LoVo cell CVCL_0399 [18]
Half Maximal Growth Inhibition (GI50) 10 nM N.A. N.A. DU145 cell CVCL_0105 [19]
Half Maximal Growth Inhibition (GI50) 10 nM N.A. N.A. HOP-62 cell CVCL_1285 [20]
Half Maximal Growth Inhibition (GI50) <10 nM N.A. N.A. UACC-62 cell CVCL_1780 [21]
Half Maximal Growth Inhibition (GI50) 10 nM N.A. N.A. UACC-62 cell CVCL_1780 [19]
Half Maximal Growth Inhibition (GI50) 10 nM N.A. N.A. MCF-7 cell CVCL_0031 [22]
Half Maximal Growth Inhibition (GI50) 10 nM N.A. N.A. SF539 cell CVCL_1691 [23]
Half Maximal Growth Inhibition (GI50) 13 nM N.A. N.A. MCF-7 cell CVCL_0031 [19]
Half Maximal Growth Inhibition (GI50) 19 nM N.A. N.A. DU145 cell CVCL_0105 [24]
Half Maximal Growth Inhibition (GI50) 20 nM N.A. N.A. SN12C cell CVCL_1705 [19]
Half Maximal Growth Inhibition (GI50) 30 nM N.A. N.A. HCT 116 cell CVCL_0291 [25]
Half Maximal Growth Inhibition (GI50) 40 nM N.A. N.A. MDA-MB-435 cell CVCL_0417 [26]
Half Maximal Growth Inhibition (GI50) 50 nM N.A. N.A. HeLa cell CVCL_0030 [27]
Half Maximal Growth Inhibition (GI50) 60 nM N.A. N.A. K562 cell CVCL_0004 [28]
Half Maximal Growth Inhibition (GI50) 80 nM N.A. N.A. HeLa cell CVCL_0030 [29]
Half Maximal Growth Inhibition (GI50) 83 nM N.A. N.A. HCT 116 cell CVCL_0291 [30]
Half Maximal Growth Inhibition (GI50) 90 nM N.A. N.A. PC-3 cell CVCL_0035 [31]
Half Maximal Growth Inhibition (GI50) 99 nM N.A. N.A. A-549 cell CVCL_0023 [32]
Half Maximal Growth Inhibition (GI50) 170 nM N.A. N.A. A-549 cell CVCL_0023 [30]
Half Maximal Growth Inhibition (GI50) 210 nM N.A. N.A. DU145 cell CVCL_0105 [32]
Half Maximal Growth Inhibition (GI50) 210 nM N.A. N.A. SW1573 cell CVCL_1720 [33]
Half Maximal Growth Inhibition (GI50) 220 nM N.A. N.A. OVCAR-3 cell CVCL_0465 [21]
Half Maximal Growth Inhibition (GI50) 230 nM N.A. N.A. HBL-100 cell CVCL_4362 [33]
Half Maximal Growth Inhibition (GI50) 280 nM N.A. N.A. MCF-7 cell CVCL_0031 [34]
Half Maximal Growth Inhibition (GI50) 460 nM N.A. N.A. A2780 cell CVCL_0134 [33]
Half Maximal Growth Inhibition (GI50) 480 nM N.A. N.A. PC-3 cell CVCL_0035 [18]
Half Maximal Growth Inhibition (GI50) 550 nM N.A. N.A. SiHa cell CVCL_0032 [35]
Half Maximal Growth Inhibition (GI50) 570 nM N.A. N.A. MCF-7 cell CVCL_0031 [28]
Half Maximal Growth Inhibition (GI50) 600 nM N.A. N.A. HeLa cell CVCL_0030 [36]
Half Maximal Growth Inhibition (GI50) >1000 nM N.A. N.A. CEM/C2 cell CVCL_3497 [16]
Half Maximal Growth Inhibition (GI50) 1.3 uM N.A. N.A. HeLa cell CVCL_0030 [18]
Half Maximal Growth Inhibition (GI50) 1.7 uM N.A. N.A. WiDr cell CVCL_2760 [33]
Half Maximal Growth Inhibition (GI50) 2.8 uM N.A. N.A. A-549 cell CVCL_0023 [29]
Half Maximal Growth Inhibition (GI50) 6 uM N.A. N.A. SAS cell CVCL_1675 [31]
Half Maximal Growth Inhibition (GI50) 6 uM N.A. N.A. MCF-7 cell CVCL_0031 [18]
Half Maximal Growth Inhibition (GI50) >287 uM N.A. N.A. PC-3 cell CVCL_0035 [30]
Half Maximal Growth Inhibition (GI50) >287 uM N.A. N.A. U2OS cell CVCL_0042 [30]
Half Maximal Inhibitory Concentration (IC50) 0.19 ug/mL N.A. N.A. HeLa cell CVCL_0030 [37]
Half Maximal Inhibitory Concentration (IC50) 1.54 ug/mL N.A. N.A. SK-OV-3 cell CVCL_0532 [38]
Half Maximal Inhibitory Concentration (IC50) 2.05 ug/mL N.A. N.A. RPMI-8226 cell CVCL_7353 [39]
Half Maximal Inhibitory Concentration (IC50) 2.72 ug/mL N.A. N.A. Bel-7402 cell CVCL_5492 [40]
Half Maximal Inhibitory Concentration (IC50) 4.63 ng/mL N.A. N.A. QG-56 cell CVCL_6943 [41]
Half Maximal Inhibitory Concentration (IC50) 4.74 ng/mL N.A. N.A. P388 cell CVCL_7222 [41]
Half Maximal Inhibitory Concentration (IC50) 5 ng/mL N.A. N.A. P388 cell CVCL_7222 [42]
Half Maximal Inhibitory Concentration (IC50) <5 ng/mL N.A. N.A. KB cell CVCL_0372 [40]
Half Maximal Inhibitory Concentration (IC50) 10 ng/mL N.A. N.A. KB cell CVCL_0372 [43]
Half Maximal Inhibitory Concentration (IC50) 14 mM N.A. N.A. DLD-1 cell CVCL_0248 [44]
Half Maximal Inhibitory Concentration (IC50) 20 ng/mL N.A. N.A. Vero cell CVCL_0059 [45]
Half Maximal Inhibitory Concentration (IC50) 40 ng/mL N.A. N.A. KB cell CVCL_0372 [43]
Half Maximal Inhibitory Concentration (IC50) 54 ng/mL N.A. N.A. Vero cell CVCL_0059 [46]
Half Maximal Inhibitory Concentration (IC50) 70 ng/mL N.A. N.A. A2780 cell CVCL_0134 [47]
Half Maximal Inhibitory Concentration (IC50) 70 ng/mL N.A. N.A. WiDr cell CVCL_2760 [37]
Half Maximal Inhibitory Concentration (IC50) 72 ng/mL N.A. N.A. A-549 cell CVCL_0023 [38]
Half Maximal Inhibitory Concentration (IC50) 90 ng/mL N.A. N.A. Hep-G2 cell CVCL_0027 [43]
Half Maximal Inhibitory Concentration (IC50) 0.32 nM N.A. N.A. Huh-7 cell CVCL_0336 [48]
Half Maximal Inhibitory Concentration (IC50) 0.32 nM N.A. N.A. LN-229 cell CVCL_0393 [48]
Half Maximal Inhibitory Concentration (IC50) 1 nM N.A. N.A. NCI-H69 cell CVCL_1579 [49]
Half Maximal Inhibitory Concentration (IC50) 1 nM N.A. N.A. A-549 cell CVCL_0023 [50]
Half Maximal Inhibitory Concentration (IC50) 1.4 nM N.A. N.A. Jurkat cell CVCL_0065 [51]
Half Maximal Inhibitory Concentration (IC50) 1.6 nM N.A. N.A. MCF-7 cell CVCL_0031 [52]
Half Maximal Inhibitory Concentration (IC50) <1.8 nM N.A. N.A. MCF-7 cell CVCL_0031 [53]
Half Maximal Inhibitory Concentration (IC50) 2 nM N.A. N.A. CCRF-CEM cell CVCL_0207 [54]
Half Maximal Inhibitory Concentration (IC50) 2 nM N.A. N.A. HCT 116 cell CVCL_0291 [55]
Half Maximal Inhibitory Concentration (IC50) 2 nM N.A. N.A. K562 cell CVCL_0004 [56]
Half Maximal Inhibitory Concentration (IC50) 3 nM N.A. N.A. CCRF-CEM cell CVCL_0207 [57]
Half Maximal Inhibitory Concentration (IC50) 3 nM N.A. N.A. CCRF-CEM cell CVCL_0207 [58]
Half Maximal Inhibitory Concentration (IC50) 3 nM N.A. N.A. MCF-7 cell CVCL_0031 [59]
Half Maximal Inhibitory Concentration (IC50) 3 nM N.A. N.A. KB cell CVCL_0372 [60]
Half Maximal Inhibitory Concentration (IC50) 3 nM N.A. N.A. SMMC-7721 cell CVCL_0534 [61]
Half Maximal Inhibitory Concentration (IC50) 3 nM N.A. N.A. HCT 15 cell CVCL_0292 [55]
Half Maximal Inhibitory Concentration (IC50) 3.1 nM N.A. N.A. MCF-7 cell CVCL_0031 [62]
Half Maximal Inhibitory Concentration (IC50) 4 nM N.A. N.A. A2780 cell CVCL_0134 [9]
Half Maximal Inhibitory Concentration (IC50) 4 nM N.A. N.A. MT4 cell CVCL_2632 [63]
Half Maximal Inhibitory Concentration (IC50) 4 nM N.A. N.A. P388 cell CVCL_7222 [64]
Half Maximal Inhibitory Concentration (IC50) 5 nM N.A. N.A. RPMI-8402 cell CVCL_1667 [65]
Half Maximal Inhibitory Concentration (IC50) 5.6 nM N.A. N.A. Jurkat cell CVCL_0065 [66]
Half Maximal Inhibitory Concentration (IC50) 6 nM N.A. N.A. RPMI-8402 cell CVCL_1667 [67]
Half Maximal Inhibitory Concentration (IC50) 6 nM N.A. N.A. RPMI-8226 cell CVCL_7353 [68]
Half Maximal Inhibitory Concentration (IC50) 6 nM N.A. N.A. T24 cell CVCL_0554 [69]
Half Maximal Inhibitory Concentration (IC50) 6 nM N.A. N.A. HL-60 cell CVCL_0002 [55]
Half Maximal Inhibitory Concentration (IC50) 6.3 nM N.A. N.A. Hep-G2 cell CVCL_0027 [70]
Half Maximal Inhibitory Concentration (IC50) 7 nM N.A. N.A. A2780 cell CVCL_0134 [71]
Half Maximal Inhibitory Concentration (IC50) 7 nM N.A. N.A. P388 cell CVCL_7222 [72]
Half Maximal Inhibitory Concentration (IC50) 8 nM N.A. N.A. A-549 cell CVCL_0023 [73]
Half Maximal Inhibitory Concentration (IC50) 8.63 nM N.A. N.A. A-549 cell CVCL_0023 [74]
Half Maximal Inhibitory Concentration (IC50) 9 nM N.A. N.A. KB cell CVCL_0372 [75]
Half Maximal Inhibitory Concentration (IC50) 9 nM N.A. N.A. HCT 116 cell CVCL_0291 [76]
Half Maximal Inhibitory Concentration (IC50) 10 nM N.A. N.A. 833K cell CVCL_2292 [77]
Half Maximal Inhibitory Concentration (IC50) <10 nM N.A. N.A. MCF-12A cell CVCL_3744 [78]
Half Maximal Inhibitory Concentration (IC50) 10 nM N.A. N.A. SK-MES-1 cell CVCL_0630 [58]
Half Maximal Inhibitory Concentration (IC50) 10 nM N.A. N.A. A-549 cell CVCL_0023 [60]
Half Maximal Inhibitory Concentration (IC50) <10 nM N.A. N.A. ZR-75-1 cell CVCL_0588 [78]
Half Maximal Inhibitory Concentration (IC50) <10 nM N.A. N.A. MCF-7 cell CVCL_0031 [78]
Half Maximal Inhibitory Concentration (IC50) <10 nM N.A. N.A. HCT 116 cell CVCL_0291 [78]
Half Maximal Inhibitory Concentration (IC50) <10 nM N.A. N.A. SK-BR-3 cell CVCL_0033 [78]
Half Maximal Inhibitory Concentration (IC50) 11.5 nM N.A. N.A. HCT 116 cell CVCL_0291 [79]
Half Maximal Inhibitory Concentration (IC50) 12 nM N.A. N.A. PC-3 cell CVCL_0035 [49]
Half Maximal Inhibitory Concentration (IC50) 13 nM N.A. N.A. P388 cell CVCL_7222 [80]
Half Maximal Inhibitory Concentration (IC50) 13 nM N.A. N.A. A-375 cell CVCL_0132 [81]
Half Maximal Inhibitory Concentration (IC50) 13 nM N.A. N.A. HL-60 cell CVCL_0002 [82]
Half Maximal Inhibitory Concentration (IC50) 14 nM N.A. N.A. P388 cell CVCL_7222 [68]
Half Maximal Inhibitory Concentration (IC50) 14 nM N.A. N.A. A-549 cell CVCL_0023 [83]
Half Maximal Inhibitory Concentration (IC50) 15 nM N.A. N.A. L1210 cell CVCL_0382 [84]
Half Maximal Inhibitory Concentration (IC50) 15 nM N.A. N.A. U-937 cell CVCL_0007 [85]
Half Maximal Inhibitory Concentration (IC50) 15.8 nM N.A. N.A. A-549 cell CVCL_0023 [86]
Half Maximal Inhibitory Concentration (IC50) 16 nM N.A. N.A. A-549 cell CVCL_0023 [87]
Half Maximal Inhibitory Concentration (IC50) 17 nM N.A. N.A. MKN45 cell CVCL_0434 [83]
Half Maximal Inhibitory Concentration (IC50) 18 nM N.A. N.A. HCT 15 cell CVCL_0292 [88]
Half Maximal Inhibitory Concentration (IC50) 18 nM N.A. N.A. HL-60 cell CVCL_0002 [89]
Half Maximal Inhibitory Concentration (IC50) 20 nM N.A. N.A. DU145 cell CVCL_0105 [90]
Half Maximal Inhibitory Concentration (IC50) 20 nM N.A. N.A. SK-OV-3 cell CVCL_0532 [83]
Half Maximal Inhibitory Concentration (IC50) 20 nM N.A. N.A. KB cell CVCL_0372 [91]
Half Maximal Inhibitory Concentration (IC50) 20 nM N.A. N.A. AGS cell CVCL_0139 [92]
Half Maximal Inhibitory Concentration (IC50) 20 nM N.A. N.A. HCT 15 cell CVCL_0292 [93]
Half Maximal Inhibitory Concentration (IC50) 20 nM N.A. N.A. HL-60 cell CVCL_0002 [94]
Half Maximal Inhibitory Concentration (IC50) 24 nM N.A. N.A. A-427 cell CVCL_1055 [62]
Half Maximal Inhibitory Concentration (IC50) 26 nM N.A. N.A. Jurkat cell CVCL_0065 [73]
Half Maximal Inhibitory Concentration (IC50) 28.4 nM N.A. N.A. MDA-MB-231 cell CVCL_0062 [95]
Half Maximal Inhibitory Concentration (IC50) 28.7 nM N.A. N.A. KB cell CVCL_0372 [96]
Half Maximal Inhibitory Concentration (IC50) 28.7 nM N.A. N.A. SW626 cell CVCL_1725 [96]
Half Maximal Inhibitory Concentration (IC50) 29 nM N.A. N.A. DU145 cell CVCL_0105 [97]
Half Maximal Inhibitory Concentration (IC50) 30 nM N.A. N.A. PC-3 cell CVCL_0035 [98]
Half Maximal Inhibitory Concentration (IC50) 30 nM N.A. N.A. L1210 cell CVCL_0382 [99]
Half Maximal Inhibitory Concentration (IC50) 30 nM N.A. N.A. NCI-H460 cell CVCL_0459 [100]
Half Maximal Inhibitory Concentration (IC50) 30 nM N.A. N.A. A-549 cell CVCL_0023 [101]
Half Maximal Inhibitory Concentration (IC50) 30 nM N.A. N.A. MCF-7 cell CVCL_0031 [101]
Half Maximal Inhibitory Concentration (IC50) 30 nM N.A. N.A. KB cell CVCL_0372 [102]
Half Maximal Inhibitory Concentration (IC50) 30 nM N.A. N.A. HCT 116 cell CVCL_0291 [101]
Half Maximal Inhibitory Concentration (IC50) 30 nM N.A. N.A. HT29 cell CVCL_A8EZ [101]
Half Maximal Inhibitory Concentration (IC50) 32 nM N.A. N.A. P388 cell CVCL_7222 [103]
Half Maximal Inhibitory Concentration (IC50) 32 nM N.A. N.A. U-937 cell CVCL_0007 [85]
Half Maximal Inhibitory Concentration (IC50) 34 nM N.A. N.A. CT26 cell CVCL_7254 [88]
Half Maximal Inhibitory Concentration (IC50) 35 nM N.A. N.A. KB cell CVCL_0372 [102]
Half Maximal Inhibitory Concentration (IC50) 37 nM N.A. N.A. KB cell CVCL_0372 [97]
Half Maximal Inhibitory Concentration (IC50) 40 nM N.A. N.A. A-549 cell CVCL_0023 [92]
Half Maximal Inhibitory Concentration (IC50) 44 nM N.A. N.A. HCC70 cell CVCL_1270 [104]
Half Maximal Inhibitory Concentration (IC50) 45 nM N.A. N.A. Col2 cell CVCL_D645 [89]
Half Maximal Inhibitory Concentration (IC50) 50 nM N.A. N.A. DU145 cell CVCL_0105 [104]
Half Maximal Inhibitory Concentration (IC50) 56 nM N.A. N.A. MCF-7 cell CVCL_0031 [105]
Half Maximal Inhibitory Concentration (IC50) 57 nM N.A. N.A. K562 cell CVCL_0004 [62]
Half Maximal Inhibitory Concentration (IC50) 58 nM N.A. N.A. A-549 cell CVCL_0023 [106]
Half Maximal Inhibitory Concentration (IC50) 60 nM N.A. N.A. MCF-7 cell CVCL_0031 [107]
Half Maximal Inhibitory Concentration (IC50) 60 nM N.A. N.A. Huh-7 cell CVCL_0336 [78]
Half Maximal Inhibitory Concentration (IC50) 65 nM N.A. N.A. HL-60 cell CVCL_0002 [108]
Half Maximal Inhibitory Concentration (IC50) 67 nM N.A. N.A. A-549 cell CVCL_0023 [109]
Half Maximal Inhibitory Concentration (IC50) 67 nM N.A. N.A. HL-60 cell CVCL_0002 [110]
Half Maximal Inhibitory Concentration (IC50) 69 nM N.A. N.A. A-549 cell CVCL_0023 [111]
Half Maximal Inhibitory Concentration (IC50) 70 nM N.A. N.A. T-47D cell CVCL_0553 [112]
Half Maximal Inhibitory Concentration (IC50) 70 nM N.A. N.A. MCF-7 cell CVCL_0031 [113]
Half Maximal Inhibitory Concentration (IC50) 70 nM N.A. N.A. KB cell CVCL_0372 [102]
Half Maximal Inhibitory Concentration (IC50) 70 nM N.A. N.A. SF268 cell CVCL_1689 [114]
Half Maximal Inhibitory Concentration (IC50) 71 nM N.A. N.A. THP-1 cell CVCL_0006 [73]
Half Maximal Inhibitory Concentration (IC50) 80 nM N.A. N.A. CCRF-CEM cell CVCL_0207 [115]
Half Maximal Inhibitory Concentration (IC50) 80 nM N.A. N.A. T-47D cell CVCL_0553 [116]
Half Maximal Inhibitory Concentration (IC50) 80 nM N.A. N.A. HT29 cell CVCL_A8EZ [109]
Half Maximal Inhibitory Concentration (IC50) 80 nM N.A. N.A. K562 cell CVCL_0004 [117]
Half Maximal Inhibitory Concentration (IC50) 86.1 nM N.A. N.A. LNCaP cell CVCL_0395 [96]
Half Maximal Inhibitory Concentration (IC50) 87.5 nM N.A. N.A. MCF-7 cell CVCL_0031 [118]
Half Maximal Inhibitory Concentration (IC50) 88 nM N.A. N.A. T24 cell CVCL_0554 [109]
Half Maximal Inhibitory Concentration (IC50) 89 nM N.A. N.A. HL-60 cell CVCL_0002 [106]
Half Maximal Inhibitory Concentration (IC50) 90 nM N.A. N.A. HeLa cell CVCL_0030 [119]
Half Maximal Inhibitory Concentration (IC50) 90 nM N.A. N.A. HCT 116 cell CVCL_0291 [120]
Half Maximal Inhibitory Concentration (IC50) 90 nM N.A. N.A. HT29 cell CVCL_A8EZ [60]
Half Maximal Inhibitory Concentration (IC50) 91 nM N.A. N.A. A-549 cell CVCL_0023 [121]
Half Maximal Inhibitory Concentration (IC50) 98 nM N.A. N.A. SNU-638 cell CVCL_0102 [122]
Half Maximal Inhibitory Concentration (IC50) 100 nM N.A. N.A. DU145 cell CVCL_0105 [123]
Half Maximal Inhibitory Concentration (IC50) 100 nM N.A. N.A. PC-3 cell CVCL_0035 [123]
Half Maximal Inhibitory Concentration (IC50) <100 nM N.A. N.A. MCF-7 cell CVCL_0031 [124]
Half Maximal Inhibitory Concentration (IC50) <100 nM N.A. N.A. Huh-7 cell CVCL_0336 [124]
Half Maximal Inhibitory Concentration (IC50) <100 nM N.A. N.A. Hep-G2 cell CVCL_0027 [124]
Half Maximal Inhibitory Concentration (IC50) 110 nM N.A. N.A. Jurkat cell CVCL_0065 [125]
Half Maximal Inhibitory Concentration (IC50) 120 nM N.A. N.A. LX-1 cell CVCL_5791 [9]
Half Maximal Inhibitory Concentration (IC50) 120 nM N.A. N.A. HCT 116 cell CVCL_0291 [126]
Half Maximal Inhibitory Concentration (IC50) 120 nM N.A. N.A. HT29 cell CVCL_A8EZ [127]
Half Maximal Inhibitory Concentration (IC50) 130 nM N.A. N.A. Hep-G2 cell CVCL_0027 [60]
Half Maximal Inhibitory Concentration (IC50) 130 nM N.A. N.A. HeLa cell CVCL_0030 [93]
Half Maximal Inhibitory Concentration (IC50) 130 nM N.A. N.A. HCT 116 cell CVCL_0291 [128]
Half Maximal Inhibitory Concentration (IC50) 130 nM N.A. N.A. K562 cell CVCL_0004 [129]
Half Maximal Inhibitory Concentration (IC50) 140 nM N.A. N.A. A-172 cell CVCL_0131 [130]
Half Maximal Inhibitory Concentration (IC50) 160 nM N.A. N.A. SW948 cell CVCL_0632 [128]
Half Maximal Inhibitory Concentration (IC50) 166 nM N.A. N.A. HCT 15 cell CVCL_0292 [121]
Half Maximal Inhibitory Concentration (IC50) 170 nM N.A. N.A. MDA-MB-361 cell CVCL_0620 [78]
Half Maximal Inhibitory Concentration (IC50) 180 nM N.A. N.A. PANC-1 cell CVCL_0480 [131]
Half Maximal Inhibitory Concentration (IC50) 180 nM N.A. N.A. MIA PaCa-2 cell CVCL_0428 [132]
Half Maximal Inhibitory Concentration (IC50) 180 nM N.A. N.A. L1210 cell CVCL_0382 [130]
Half Maximal Inhibitory Concentration (IC50) 180 nM N.A. N.A. NCI-H460 cell CVCL_0459 [133]
Half Maximal Inhibitory Concentration (IC50) 180 nM N.A. N.A. HeLa cell CVCL_0030 [90]
Half Maximal Inhibitory Concentration (IC50) 200 nM N.A. N.A. MCF-7 cell CVCL_0031 [60]
Half Maximal Inhibitory Concentration (IC50) 200 nM N.A. N.A. Hep-G2 cell CVCL_0027 [134]
Half Maximal Inhibitory Concentration (IC50) 210 nM N.A. N.A. BGC-823 cell CVCL_3360 [135]
Half Maximal Inhibitory Concentration (IC50) 210 nM N.A. N.A. SW480 cell CVCL_0546 [136]
Half Maximal Inhibitory Concentration (IC50) 210 nM N.A. N.A. DLD-1 cell CVCL_0248 [137]
Half Maximal Inhibitory Concentration (IC50) 240 nM N.A. N.A. BxPC-3 cell CVCL_0186 [60]
Half Maximal Inhibitory Concentration (IC50) 260 nM N.A. N.A. A2780 cell CVCL_0134 [138]
Half Maximal Inhibitory Concentration (IC50) 260 nM N.A. N.A. A-549 cell CVCL_0023 [126]
Half Maximal Inhibitory Concentration (IC50) 260 nM N.A. N.A. Bel-7402 cell CVCL_5492 [138]
Half Maximal Inhibitory Concentration (IC50) 260 nM N.A. N.A. HT29 cell CVCL_A8EZ [49]
Half Maximal Inhibitory Concentration (IC50) 260 nM N.A. N.A. HCT 15 cell CVCL_0292 [139]
Half Maximal Inhibitory Concentration (IC50) 280 nM N.A. N.A. SNU-638 cell CVCL_0102 [140]
Half Maximal Inhibitory Concentration (IC50) 290 nM N.A. N.A. SW480 cell CVCL_0546 [141]
Half Maximal Inhibitory Concentration (IC50) 291 nM N.A. N.A. MDA-MB-231 cell CVCL_0062 [69]
Half Maximal Inhibitory Concentration (IC50) 300 nM N.A. N.A. Hep-G2 cell CVCL_0027 [142]
Half Maximal Inhibitory Concentration (IC50) 304 nM N.A. N.A. Renca cell CVCL_2174 [88]
Half Maximal Inhibitory Concentration (IC50) 307 nM N.A. N.A. MDA-MB-231 cell CVCL_0062 [74]
Half Maximal Inhibitory Concentration (IC50) 320 nM N.A. N.A. MCF-7 cell CVCL_0031 [143]
Half Maximal Inhibitory Concentration (IC50) 330 nM N.A. N.A. L1210 cell CVCL_0382 [144]
Half Maximal Inhibitory Concentration (IC50) 340 nM N.A. N.A. CNE cell CVCL_6888 [145]
Half Maximal Inhibitory Concentration (IC50) 370 nM N.A. N.A. Hep-G2 cell CVCL_0027 [146]
Half Maximal Inhibitory Concentration (IC50) 400 nM N.A. N.A. DU145 cell CVCL_0105 [147]
Half Maximal Inhibitory Concentration (IC50) 400 nM N.A. N.A. PC-3 cell CVCL_0035 [94]
Half Maximal Inhibitory Concentration (IC50) 400 nM N.A. N.A. MIA PaCa-2 cell CVCL_0428 [148]
Half Maximal Inhibitory Concentration (IC50) 400 nM N.A. N.A. HeLa cell CVCL_0030 [149]
Half Maximal Inhibitory Concentration (IC50) 400 nM N.A. N.A. K562 cell CVCL_0004 [150]
Half Maximal Inhibitory Concentration (IC50) 420 nM N.A. N.A. HeLa cell CVCL_0030 [125]
Half Maximal Inhibitory Concentration (IC50) 430 nM N.A. N.A. IMR-90 cell CVCL_0347 [114]
Half Maximal Inhibitory Concentration (IC50) 450 nM N.A. N.A. SMMC-7721 cell CVCL_0534 [141]
Half Maximal Inhibitory Concentration (IC50) 490 nM N.A. N.A. T-47D cell CVCL_0553 [93]
Half Maximal Inhibitory Concentration (IC50) 500 nM N.A. N.A. HeLa cell CVCL_0030 [151]
Half Maximal Inhibitory Concentration (IC50) 500 nM N.A. N.A. HCT 15 cell CVCL_0292 [152]
Half Maximal Inhibitory Concentration (IC50) 520 nM N.A. N.A. CA46 cell CVCL_1101 [153]
Half Maximal Inhibitory Concentration (IC50) 540 nM N.A. N.A. MDA-MB-231 cell CVCL_0062 [154]
Half Maximal Inhibitory Concentration (IC50) 580 nM N.A. N.A. HeLa cell CVCL_0030 [110]
Half Maximal Inhibitory Concentration (IC50) 590 nM N.A. N.A. K562 cell CVCL_0004 [155]
Half Maximal Inhibitory Concentration (IC50) 600 nM N.A. N.A. HCT 15 cell CVCL_0292 [119]
Half Maximal Inhibitory Concentration (IC50) 600 nM N.A. N.A. HL-60 cell CVCL_0002 [73]
Half Maximal Inhibitory Concentration (IC50) 610 nM N.A. N.A. DU145 cell CVCL_0105 [155]
Half Maximal Inhibitory Concentration (IC50) 630 nM N.A. N.A. HeLa cell CVCL_0030 [107]
Half Maximal Inhibitory Concentration (IC50) 660 nM N.A. N.A. DU145 cell CVCL_0105 [107]
Half Maximal Inhibitory Concentration (IC50) 680 nM N.A. N.A. U-937 cell CVCL_0007 [85]
Half Maximal Inhibitory Concentration (IC50) 700 nM N.A. N.A. A-549 cell CVCL_0023 [156]
Half Maximal Inhibitory Concentration (IC50) 711 nM N.A. N.A. K562 cell CVCL_0004 [94]
Half Maximal Inhibitory Concentration (IC50) 760 nM N.A. N.A. HCT 15 cell CVCL_0292 [107]
Half Maximal Inhibitory Concentration (IC50) 800 nM N.A. N.A. DU145 cell CVCL_0105 [150]
Half Maximal Inhibitory Concentration (IC50) 800 nM N.A. N.A. NCI-H1299 cell CVCL_0060 [156]
Half Maximal Inhibitory Concentration (IC50) 800 nM N.A. N.A. HCT 15 cell CVCL_0292 [155]
Half Maximal Inhibitory Concentration (IC50) 800 nM N.A. N.A. HL-60 cell CVCL_0002 [157]
Half Maximal Inhibitory Concentration (IC50) 850 nM N.A. N.A. HT29 cell CVCL_A8EZ [108]
Half Maximal Inhibitory Concentration (IC50) 860 nM N.A. N.A. HeLa cell CVCL_0030 [108]
Half Maximal Inhibitory Concentration (IC50) 890 nM N.A. N.A. MRC5 cell CVCL_0440 [100]
Half Maximal Inhibitory Concentration (IC50) 940 nM N.A. N.A. HeLa cell CVCL_0030 [158]
Half Maximal Inhibitory Concentration (IC50) 950 nM N.A. N.A. DU145 cell CVCL_0105 [159]
Half Maximal Inhibitory Concentration (IC50) 980 nM N.A. N.A. CNE-2 cell CVCL_6889 [145]
Half Maximal Inhibitory Concentration (IC50) 1000 nM N.A. N.A. DU145 cell CVCL_0105 [110]
Half Maximal Inhibitory Concentration (IC50) >1000 nM N.A. N.A. NCI-H460 cell CVCL_0459 [49]
Half Maximal Inhibitory Concentration (IC50) <1000 nM N.A. N.A. Hep-G2 cell CVCL_0027 [160]
Half Maximal Inhibitory Concentration (IC50) 1000 nM N.A. N.A. Raji cell CVCL_0511 [161]
Half Maximal Inhibitory Concentration (IC50) <1000 nM N.A. N.A. HCT 116 cell CVCL_0291 [162]
Half Maximal Inhibitory Concentration (IC50) 1000 nM N.A. N.A. HCT 116 cell CVCL_0291 [82]
Half Maximal Inhibitory Concentration (IC50) 1.01 uM N.A. N.A. HeLa cell CVCL_0030 [163]
Half Maximal Inhibitory Concentration (IC50) 1.04 uM N.A. N.A. KB cell CVCL_0372 [102]
Half Maximal Inhibitory Concentration (IC50) 1.07 uM N.A. N.A. HT29 cell CVCL_A8EZ [110]
Half Maximal Inhibitory Concentration (IC50) 1.08 uM N.A. N.A. SMMC-7721 cell CVCL_0534 [145]
Half Maximal Inhibitory Concentration (IC50) 1.08 uM N.A. N.A. HeLa cell CVCL_0030 [164]
Half Maximal Inhibitory Concentration (IC50) 1.1 uM N.A. N.A. MCF-7 cell CVCL_0031 [92]
Half Maximal Inhibitory Concentration (IC50) 1.1 uM N.A. N.A. HeLa cell CVCL_0030 [165]
Half Maximal Inhibitory Concentration (IC50) 1.18 uM N.A. N.A. K562 cell CVCL_0004 [163]
Half Maximal Inhibitory Concentration (IC50) 1.22 uM N.A. N.A. MCF-7 cell CVCL_0031 [166]
Half Maximal Inhibitory Concentration (IC50) 1.22 uM N.A. N.A. HeLa cell CVCL_0030 [166]
Half Maximal Inhibitory Concentration (IC50) 1.37 uM N.A. N.A. HeLa cell CVCL_0030 [112]
Half Maximal Inhibitory Concentration (IC50) 1.4 uM N.A. N.A. HT29 cell CVCL_A8EZ [167]
Half Maximal Inhibitory Concentration (IC50) 1.4144 uM N.A. N.A. PC-3 cell CVCL_0035 [168]
Half Maximal Inhibitory Concentration (IC50) 1.46 uM N.A. N.A. DU145 cell CVCL_0105 [169]
Half Maximal Inhibitory Concentration (IC50) 1.59 uM N.A. N.A. HeLa cell CVCL_0030 [170]
Half Maximal Inhibitory Concentration (IC50) 1.6 uM N.A. N.A. A-549 cell CVCL_0023 [153]
Half Maximal Inhibitory Concentration (IC50) 1.61 uM N.A. N.A. HEK293 cell CVCL_0045 [171]
Half Maximal Inhibitory Concentration (IC50) 1.62 uM N.A. N.A. T-47D cell CVCL_0553 [170]
Half Maximal Inhibitory Concentration (IC50) 1.7 uM N.A. N.A. MX1 cell CVCL_4774 [172]
Half Maximal Inhibitory Concentration (IC50) 1.8 uM N.A. N.A. MCF-7 cell CVCL_0031 [173]
Half Maximal Inhibitory Concentration (IC50) 1.84 uM N.A. N.A. T-47D cell CVCL_0553 [174]
Half Maximal Inhibitory Concentration (IC50) 1.88 uM N.A. N.A. HCT 116 cell CVCL_0291 [171]
Half Maximal Inhibitory Concentration (IC50) 1.98 uM N.A. N.A. U-937 cell CVCL_0007 [73]
Half Maximal Inhibitory Concentration (IC50) 2 uM N.A. N.A. HT29 cell CVCL_A8EZ [142]
Half Maximal Inhibitory Concentration (IC50) 2.21 uM N.A. N.A. A-549 cell CVCL_0023 [175]
Half Maximal Inhibitory Concentration (IC50) 2.3 uM N.A. N.A. HCT 116 cell CVCL_0291 [165]
Half Maximal Inhibitory Concentration (IC50) 2.31 uM N.A. N.A. T-47D cell CVCL_0553 [176]
Half Maximal Inhibitory Concentration (IC50) 2.5 uM N.A. N.A. PC-3 cell CVCL_0035 [120]
Half Maximal Inhibitory Concentration (IC50) 2.53 uM N.A. N.A. A-549 cell CVCL_0023 [167]
Half Maximal Inhibitory Concentration (IC50) 2.544 uM N.A. N.A. SK-OV-3 cell CVCL_0532 [121]
Half Maximal Inhibitory Concentration (IC50) 2.7 uM N.A. N.A. MDA-MB-231 cell CVCL_0062 [173]
Half Maximal Inhibitory Concentration (IC50) 3.04 uM N.A. N.A. HEp-2 cell CVCL_1906 [177]
Half Maximal Inhibitory Concentration (IC50) 3.09 uM N.A. N.A. T24 cell CVCL_0554 [178]
Half Maximal Inhibitory Concentration (IC50) 3.1 uM N.A. N.A. A-549 cell CVCL_0023 [179]
Half Maximal Inhibitory Concentration (IC50) 3.1 uM N.A. N.A. LoVo cell CVCL_0399 [180]
Half Maximal Inhibitory Concentration (IC50) 3.2 uM N.A. N.A. DU145 cell CVCL_0105 [165]
Half Maximal Inhibitory Concentration (IC50) 3.57 uM N.A. N.A. DU145 cell CVCL_0105 [108]
Half Maximal Inhibitory Concentration (IC50) 3.6 uM N.A. N.A. A-549 cell CVCL_0023 [181]
Half Maximal Inhibitory Concentration (IC50) 3.8 uM N.A. N.A. HeLa cell CVCL_0030 [182]
Half Maximal Inhibitory Concentration (IC50) 3.97 uM N.A. N.A. HCT 116 cell CVCL_0291 [164]
Half Maximal Inhibitory Concentration (IC50) 4.16 uM N.A. N.A. MDA-MB-231 cell CVCL_0062 [82]
Half Maximal Inhibitory Concentration (IC50) 4.2 uM N.A. N.A. MDA-MB-231 cell CVCL_0062 [165]
Half Maximal Inhibitory Concentration (IC50) 4.79 uM N.A. N.A. Hep-G2 cell CVCL_0027 [183]
Half Maximal Inhibitory Concentration (IC50) 5.5 uM N.A. N.A. SK-OV-3 cell CVCL_0532 [184]
Half Maximal Inhibitory Concentration (IC50) 5.5 uM N.A. N.A. A-549 cell CVCL_0023 [185]
Half Maximal Inhibitory Concentration (IC50) 5.93 uM N.A. N.A. A-549 cell CVCL_0023 [177]
Half Maximal Inhibitory Concentration (IC50) 6.08 uM N.A. N.A. HCT 15 cell CVCL_0292 [170]
Half Maximal Inhibitory Concentration (IC50) 6.4 uM N.A. N.A. Hep-G2 cell CVCL_0027 [186]
Half Maximal Inhibitory Concentration (IC50) 6.96 uM N.A. N.A. PC-3 cell CVCL_0035 [187]
Half Maximal Inhibitory Concentration (IC50) 7.42 uM N.A. N.A. MCF-7 cell CVCL_0031 [169]
Half Maximal Inhibitory Concentration (IC50) 7.94 uM N.A. N.A. HEK293 cell CVCL_0045 [188]
Half Maximal Inhibitory Concentration (IC50) 8.81 uM N.A. N.A. HT29 cell CVCL_A8EZ [133]
Half Maximal Inhibitory Concentration (IC50) 8.87 uM N.A. N.A. A-549 cell CVCL_0023 [189]
Half Maximal Inhibitory Concentration (IC50) 9.17 uM N.A. N.A. T-47D cell CVCL_0553 [188]
Half Maximal Inhibitory Concentration (IC50) 9.29 uM N.A. N.A. DU145 cell CVCL_0105 [188]
Half Maximal Inhibitory Concentration (IC50) 9.55 uM N.A. N.A. Caco-2 cell CVCL_0025 [190]
Half Maximal Inhibitory Concentration (IC50) 9.92 uM N.A. N.A. HCT 15 cell CVCL_0292 [188]
Half Maximal Inhibitory Concentration (IC50) 10 uM N.A. N.A. MCF-7 cell CVCL_0031 [142]
Half Maximal Inhibitory Concentration (IC50) 10.1 uM N.A. N.A. HeLa cell CVCL_0030 [191]
Half Maximal Inhibitory Concentration (IC50) 11.17 uM N.A. N.A. T-47D cell CVCL_0553 [192]
Half Maximal Inhibitory Concentration (IC50) 12.5 uM N.A. N.A. Bel-7402 cell CVCL_5492 [193]
Half Maximal Inhibitory Concentration (IC50) 13.62 uM N.A. N.A. MCF-7 cell CVCL_0031 [189]
Half Maximal Inhibitory Concentration (IC50) 13.64 uM N.A. N.A. A-549 cell CVCL_0023 [191]
Half Maximal Inhibitory Concentration (IC50) 14 uM N.A. N.A. HeLa cell CVCL_0030 [153]
Half Maximal Inhibitory Concentration (IC50) 14.2 uM N.A. N.A. MCF-7 cell CVCL_0031 [165]
Half Maximal Inhibitory Concentration (IC50) 14.76 uM N.A. N.A. MDA-MB-468 cell CVCL_0419 [194]
Half Maximal Inhibitory Concentration (IC50) 18.24 uM N.A. N.A. PC-3 cell CVCL_0035 [175]
Half Maximal Inhibitory Concentration (IC50) 23.76 uM N.A. N.A. AGS cell CVCL_0139 [195]
Half Maximal Inhibitory Concentration (IC50) >40 uM N.A. N.A. PC-3 cell CVCL_0035 [94]
Half Maximal Inhibitory Concentration (IC50) >40 uM N.A. N.A. BJ cell CVCL_E483 [94]
Half Maximal Inhibitory Concentration (IC50) >40 uM N.A. N.A. TERT-RPE1 cell CVCL_4388 [94]
Half Maximal Inhibitory Concentration (IC50) 51.5 uM N.A. N.A. Jurkat cell CVCL_0065 [196]
Half Maximal Inhibitory Concentration (IC50) 60.01 uM N.A. N.A. HeLa cell CVCL_0030 [197]
Half Maximal Inhibitory Concentration (IC50) 130 uM N.A. N.A. HL-60 cell CVCL_0002 [198]
Half Maximal Lethal Concentration (IC50) 31.62 uM N.A. N.A. HT29 cell CVCL_A8EZ [199]
Half Maximal Lethal Concentration (IC50) >100 uM N.A. N.A. MCF-7 cell CVCL_0031 [200]
Half Maximal Lethal Concentration (IC50) >100 uM N.A. N.A. K562 cell CVCL_0004 [199]
Tumor Growth Inhibition value (TGI) 160 nM N.A. N.A. MCF-7 cell CVCL_0031 [200]
Tumor Growth Inhibition value (TGI) 31.62 uM N.A. N.A. HT29 cell CVCL_A8EZ [199]
Tumor Growth Inhibition value (TGI) 50.12 uM N.A. N.A. K562 cell CVCL_0004 [199]
Each Peptide-drug Conjugate Related to This Drug
Full Information of The Activity Data of The PDC(s) Related to This Drug
PDC-Z8 [Investigative]
 PDC Info 
Discovered Using Cell Line-derived Xenograft Model
Click To Hide/Show 1 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Tumor Growth Inhibition value (TGI) 60% (Day 14)
Administration Time Injected via tail vein every t hree days
Administration Dosage 8 µmol/kg
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To study the in vivo anti-tumor activity of Z8, SK-BR-3 tumor bearing nude mice were administered once every three days. As shown in Fig. 11A-11D, CPT and Z8 demonstrated significant inhibitory effects on SK-BR-3 tumor growth, with the Z8 group exhibiting more pronounced inhibition compared to CPT. Notably, the average tumor volume and weight in the Z8 group were the smallest among all groups, including the control and CPT groups. Moreover, to further study the toxicity of CPT and Z8, serums of mice were collected for blood biochemical analysis. As shown in Fig. 11E-H, treatment with both CPT and Z8 resulted in increased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), but the effect of Z8 group was relatively low, indicating that Z8 was safer than CPT in vivo. Furthermore, in CPT group, urea nitrogen levels increased significantly, whereas no significant change was observed in the Z8 group, indicating potential renal function impairment following CPT treatment, whereas Z8 showed better safety in this regard. Additionally, the levels of alkaline phosphatase (ALP), total protein (TP), albumin (ALB), globulin (GLOB) and creatinine (CREA) did not significantly differ between the control group and the treatment groups. Finally, compared to the control group, histological examination using H&E staining (Hematoxylin and Eosin staining) of the major organs in the treatment group did not reveal obvious cell necrosis and inflammatory cell infiltration, indicating that Z8 would not bring additional toxicity.

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In Vivo Model SK-BR-3 tumor-bearing nude mice xenograft model.
In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Revealed Based on the Cell Line Data
Click To Hide/Show 6 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 1.04 ± 0.24 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 2 Reporting the Activity Data of This PDC [1]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 1.91 ± 0.71 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
Experiment 3 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 13.49 ± 3.59 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Breast adenocarcinoma MDA-MB-231 cell CVCL_0062
Experiment 4 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 26.34 ± 1.08 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Normal MCF-10A cell CVCL_0598
Experiment 5 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Apoptosis rate 27.10%
Evaluation Method Flow cytometry assay
Administration Time 24 h
Administration Dosage 1 µM
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
The proapoptotic activity of Z8 was studied by flow cytometry combined with Annexin V-FITC/PI double staining. As shown in Fig. 4, after treatment with 1 uM Z8, the apoptosis rate of SK-BR-3 cells was approximately 27.1 % which increased to 41.1 % following treatment with 2 uM Z8 (4.4 % in the blank control group and 55.8 % in CPT group. These findings suggest that Z8 can significantly induce apoptosis in a dose-dependent manner.

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In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 6 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Apoptosis rate 41.10%
Evaluation Method Flow cytometry assay
Administration Time 24 h
Administration Dosage 2 µM
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
The proapoptotic activity of Z8 was studied by flow cytometry combined with Annexin V-FITC/PI double staining. As shown in Fig. 4, after treatment with 1 uM Z8, the apoptosis rate of SK-BR-3 cells was approximately 27.1 % which increased to 41.1 % following treatment with 2 uM Z8 (4.4 % in the blank control group and 55.8 % in CPT group. These findings suggest that Z8 can significantly induce apoptosis in a dose-dependent manner.

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In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
diCPTiRGD [Investigative]
 PDC Info 
Discovered Using Cell Line-derived Xenograft Model
Click To Hide/Show 2 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [201]
Indication Solid tumor
Efficacy Data Tumer volume 0 mm3
Administration Time 30 days
MOA of PDC
In this context, we developed a drug-bearing supramolecular hydrogel system to intratumourally (i.t.) deliver CDNs against malignant tumours to achieve cancer chemoimmunotherapy. Our strategy was to chemically conjugate the hydrophilic pep-tide moiety iRGD (a tumour-penetrating peptide that can bind to neuropilin-1 (NRP-1) and trigger tumour tissue penetration) to the hydrophobic anticancer drug CPT to form a self-assembling and self-formulating peptide-drug conjugate (diCPT-iRGD). In aqueous solution, the designed drug amphiphile spontaneously assembles into supramolecular nanotubes (NTs). The negatively charged STING agonist (c-di-AMP (CDA)) can condense on the surface of these positively charged NTs through electrostatic complexations. After injection into the tumour site, the CDA-NT solution can immediately form a hydrogel, functioning as a local reservoir for extended localized release of CDA and CPT to awaken both the innate and adaptive immune systems.

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Description
When using the diCPT-iRGD NT hydrogel, the CDA-NT treatment led to substantial tumour regression (Fig. 3c-e) and demonstrated a 100% survival rate in mice (Fig. 3f).
In Vivo Model GL-261 brain cancer C57BL/6 mice.
Experiment 2 Reporting the Activity Data of This PDC [201]
Indication Solid tumor
Efficacy Data Survival rate 100.00%
Administration Time 30 days
MOA of PDC
In this context, we developed a drug-bearing supramolecular hydrogel system to intratumourally (i.t.) deliver CDNs against malignant tumours to achieve cancer chemoimmunotherapy. Our strategy was to chemically conjugate the hydrophilic pep-tide moiety iRGD (a tumour-penetrating peptide that can bind to neuropilin-1 (NRP-1) and trigger tumour tissue penetration) to the hydrophobic anticancer drug CPT to form a self-assembling and self-formulating peptide-drug conjugate (diCPT-iRGD). In aqueous solution, the designed drug amphiphile spontaneously assembles into supramolecular nanotubes (NTs). The negatively charged STING agonist (c-di-AMP (CDA)) can condense on the surface of these positively charged NTs through electrostatic complexations. After injection into the tumour site, the CDA-NT solution can immediately form a hydrogel, functioning as a local reservoir for extended localized release of CDA and CPT to awaken both the innate and adaptive immune systems.

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Description
When using the diCPT-iRGD NT hydrogel, the CDA-NT treatment led to substantial tumour regression (Fig. 3c-e) and demonstrated a 100% survival rate in mice (Fig. 3f).
In Vivo Model GL-261 brain cancer C57BL/6 mice.
JF-10-71 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 1 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [202], [203]
Indication Neuroblastoma
Efficacy Data Half maximal inhibitory concentration (IC50) 1363 nM
Evaluation Method MTT assay
Administration Time 3 days
MOA of PDC
In a previous study, we used a potent somatostatin analog (SSA) with high affinity for SSTR2 for attachment to an antisense peptide nucleic acid (PNA) directed against the n-myc oncogene and showed that PNA-SSA conjugates produced receptor-specific inhibition of cell growth. Cleavable-linker chemistry was then developed that allowed this approach to be extended to well-known cytotoxic compounds such as camptothecin and combretastatin. In the present report two CPT-SSA conjugates, JF-10-71 and JF-10-81, displaying differing stabilities were chosen to potentially treat SSTR2-positive rat pancreatic CA20948 tumors in Lewis rats and SCLC NCI-H69 tumors in athymic nude mice.

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Description
Previously, a series of CPT-SSA conjugates were tested for their stability in phosphate buffer/rat plasma and in vitro inhibitory activity in tumor cell growth (data not shown). Two of these conjugates, JF-10-71 and JF-10-81, displaying higher and lower stability, respectively, were chosen for further experiments in serial tumor cell lines. Also, free CPT and SSA itself were tested as controls. The results (Table 1) show that the IC50 values increased compared with CPT to JF-10-81 and further to JF-10-71 with the exception of the CA20948 cells. CPT and both conjugates were particularly effective in SSTR2-overexpressing IMR32 cells displaying IC50 values 3.1, 64.13, and 282.50 nM, respectively. SSTR2-overexpressing CA20948 cells were poorly responsive to CPT itself (IC50, 3077 nM); however, its somatostatin conjugates were actually more potent (IC50: JF-10-81, 1790 nM; JF-10-71, 1363 nM). SSA itself exhibited little effect on growth of all tested cell lines even at doses up to 10-5 M.

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JF-10-81 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 1 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [202], [203]
Indication Neuroblastoma
Efficacy Data Half maximal inhibitory concentration (IC50) 1790 nM
Evaluation Method MTT assay
Administration Time 3 days
MOA of PDC
In a previous study, we used a potent somatostatin analog (SSA) with high affinity for SSTR2 for attachment to an antisense peptide nucleic acid (PNA) directed against the n-myc oncogene and showed that PNA-SSA conjugates produced receptor-specific inhibition of cell growth. Cleavable-linker chemistry was then developed that allowed this approach to be extended to well-known cytotoxic compounds such as camptothecin and combretastatin. In the present report two CPT-SSA conjugates, JF-10-71 and JF-10-81, displaying differing stabilities were chosen to potentially treat SSTR2-positive rat pancreatic CA20948 tumors in Lewis rats and SCLC NCI-H69 tumors in athymic nude mice.

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Description
Previously, a series of CPT-SSA conjugates were tested for their stability in phosphate buffer/rat plasma and in vitro inhibitory activity in tumor cell growth (data not shown). Two of these conjugates, JF-10-71 and JF-10-81, displaying higher and lower stability, respectively, were chosen for further experiments in serial tumor cell lines. Also, free CPT and SSA itself were tested as controls. The results (Table 1) show that the IC50 values increased compared with CPT to JF-10-81 and further to JF-10-71 with the exception of the CA20948 cells. CPT and both conjugates were particularly effective in SSTR2-overexpressing IMR32 cells displaying IC50 values 3.1, 64.13, and 282.50 nM, respectively. SSTR2-overexpressing CA20948 cells were poorly responsive to CPT itself (IC50, 3077 nM); however, its somatostatin conjugates were actually more potent (IC50: JF-10-81, 1790 nM; JF-10-71, 1363 nM). SSA itself exhibited little effect on growth of all tested cell lines even at doses up to 10-5 M.

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Kb-CC07 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 9 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [3]
Indication Colon cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 0.11 ± 0.01 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

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Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Colon carcinoma HCT 116 cell CVCL_0291
Experiment 2 Reporting the Activity Data of This PDC [3]
Indication Colon cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 0.23 ± 0.01 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

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Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Colon carcinoma HCT-116/CPT cell CVCL_0291
Experiment 3 Reporting the Activity Data of This PDC [3]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 0.33 ± 0.02 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

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Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Gastric carcinoma SGC-7901 cell CVCL_0520
Experiment 4 Reporting the Activity Data of This PDC [3]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 0.42 ± 0.01 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

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Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Invasive breast carcinoma MCF-7 cell CVCL_0031
Experiment 5 Reporting the Activity Data of This PDC [3]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 0.80 ± 0.08 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

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Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Human papillomavirus-related cervical adenocarcinoma SGC-7901/CPT cell CVCL_0520
Experiment 6 Reporting the Activity Data of This PDC [3]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 1.01 ± 0.05 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

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Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Invasive breast carcinoma of no special type MCF7/C4 cell CVCL_GX99
Experiment 7 Reporting the Activity Data of This PDC [3]
Indication Colon cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 13.7 ± 1.1 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

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Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Normal NCM460 cell CVCL_0460
Experiment 8 Reporting the Activity Data of This PDC [3]
Indication Liver cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 15.5 ± 1.0 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

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Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Amelanotic melanoma LO #2 cell CVCL_C7SD
Experiment 9 Reporting the Activity Data of This PDC [3]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 17.3 ± 0.8 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

   Click to Show/Hide
Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Normal GES1 cell CVCL_EQ22
I-4 (NPNWGRSWYNQRFKGC=(-SS-O-COO-CPT)GC=(-SS-O-COO-CPT)GRIKPRKGYTR) [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 5 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [4]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 0.12 ± 0.07 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

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Description
The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 ± 0.54, 3.29 ± 0.67, and 4.29 ± 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 ± 0.07, 1.78 ± 0.47, and 1.27 ± 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 ± 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 ± 1.23 and 7.72 ± 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 ± 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 ± 1.58 and 17.14 ± 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 ± 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation.

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In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 2 Reporting the Activity Data of This PDC [4]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 1.27 ± 0.38 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

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Description
The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 ± 0.54, 3.29 ± 0.67, and 4.29 ± 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 ± 0.07, 1.78 ± 0.47, and 1.27 ± 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 ± 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 ± 1.23 and 7.72 ± 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 ± 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 ± 1.58 and 17.14 ± 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 ± 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation.

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In Vitro Model Ovarian serous cystadenocarcinoma SK-OV-3 cell CVCL_0532
Experiment 3 Reporting the Activity Data of This PDC [4]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 1.78 ± 0.47 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

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Description
The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 ± 0.54, 3.29 ± 0.67, and 4.29 ± 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 ± 0.07, 1.78 ± 0.47, and 1.27 ± 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 ± 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 ± 1.23 and 7.72 ± 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 ± 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 ± 1.58 and 17.14 ± 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 ± 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation.

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In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
Experiment 4 Reporting the Activity Data of This PDC [4]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 7.72 ± 0.92 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

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Description
The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 ± 0.54, 3.29 ± 0.67, and 4.29 ± 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 ± 0.07, 1.78 ± 0.47, and 1.27 ± 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 ± 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 ± 1.23 and 7.72 ± 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 ± 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 ± 1.58 and 17.14 ± 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 ± 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation.

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In Vitro Model Breast adenocarcinoma MDA-MB-231 cell CVCL_0062
Experiment 5 Reporting the Activity Data of This PDC [4]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 17.14 ± 2.42 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

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Description
The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 ± 0.54, 3.29 ± 0.67, and 4.29 ± 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 ± 0.07, 1.78 ± 0.47, and 1.27 ± 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 ± 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 ± 1.23 and 7.72 ± 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 ± 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 ± 1.58 and 17.14 ± 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 ± 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation.

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In Vitro Model Normal MCF-10A cell CVCL_0598
Kb-CC04 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 9 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [3]
Indication Colon cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 0.14 ± 0.02 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

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Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Colon carcinoma HCT 116 cell CVCL_0291
Experiment 2 Reporting the Activity Data of This PDC [3]
Indication Colon cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 0.32 ± 0.02 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

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Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Colon carcinoma HCT-116/CPT cell CVCL_0291
Experiment 3 Reporting the Activity Data of This PDC [3]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 0.38 ± 0.01 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

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Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Gastric carcinoma SGC-7901 cell CVCL_0520
Experiment 4 Reporting the Activity Data of This PDC [3]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 0.43 ± 0.02 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

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Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Invasive breast carcinoma MCF-7 cell CVCL_0031
Experiment 5 Reporting the Activity Data of This PDC [3]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 1.00 ± 0.08 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

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Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Human papillomavirus-related cervical adenocarcinoma SGC-7901/CPT cell CVCL_0520
Experiment 6 Reporting the Activity Data of This PDC [3]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 1.05 ± 0.03 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

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Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Invasive breast carcinoma of no special type MCF7/C4 cell CVCL_GX99
Experiment 7 Reporting the Activity Data of This PDC [3]
Indication Colon cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 13.4 ± 0.4 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

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Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Normal NCM460 cell CVCL_0460
Experiment 8 Reporting the Activity Data of This PDC [3]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 15.5 ± 0.6 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

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Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Normal GES1 cell CVCL_EQ22
Experiment 9 Reporting the Activity Data of This PDC [3]
Indication Liver cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 16.4 ± 0.2 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

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Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Amelanotic melanoma LO #2 cell CVCL_C7SD
Kb-CC08 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 9 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [3]
Indication Colon cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 0.14 ± 0.02 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

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Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Colon carcinoma HCT 116 cell CVCL_0291
Experiment 2 Reporting the Activity Data of This PDC [3]
Indication Colon cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 0.35 ± 0.02 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

   Click to Show/Hide
Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Colon carcinoma HCT-116/CPT cell CVCL_0291
Experiment 3 Reporting the Activity Data of This PDC [3]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 0.41 ± 0.02 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

   Click to Show/Hide
Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Invasive breast carcinoma MCF-7 cell CVCL_0031
Experiment 4 Reporting the Activity Data of This PDC [3]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 0.47 ± 0.01 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

   Click to Show/Hide
Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Gastric carcinoma SGC-7901 cell CVCL_0520
Experiment 5 Reporting the Activity Data of This PDC [3]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 1.03 ± 0.06 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

   Click to Show/Hide
Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Invasive breast carcinoma of no special type MCF7/C4 cell CVCL_GX99
Experiment 6 Reporting the Activity Data of This PDC [3]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 1.06 ± 0.07 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

   Click to Show/Hide
Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Human papillomavirus-related cervical adenocarcinoma SGC-7901/CPT cell CVCL_0520
Experiment 7 Reporting the Activity Data of This PDC [3]
Indication Colon cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 14.8 ± 0.9 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

   Click to Show/Hide
Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Normal NCM460 cell CVCL_0460
Experiment 8 Reporting the Activity Data of This PDC [3]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 15.2 ± 0.7 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

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Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Normal GES1 cell CVCL_EQ22
Experiment 9 Reporting the Activity Data of This PDC [3]
Indication Liver cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 16.1 ± 0.5 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

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Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Amelanotic melanoma LO #2 cell CVCL_C7SD
Kb-CC03 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 9 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [3]
Indication Colon cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 0.15 ± 0.03 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

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Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Colon carcinoma HCT 116 cell CVCL_0291
Experiment 2 Reporting the Activity Data of This PDC [3]
Indication Colon cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 0.35 ± 0.03 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

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Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Colon carcinoma HCT-116/CPT cell CVCL_0291
Experiment 3 Reporting the Activity Data of This PDC [3]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 0.42 ± 0.01 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

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Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Invasive breast carcinoma MCF-7 cell CVCL_0031
Experiment 4 Reporting the Activity Data of This PDC [3]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 0.46 ± 0.02 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

   Click to Show/Hide
Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Gastric carcinoma SGC-7901 cell CVCL_0520
Experiment 5 Reporting the Activity Data of This PDC [3]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 1.03 ± 0.03 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

   Click to Show/Hide
Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Invasive breast carcinoma of no special type MCF7/C4 cell CVCL_GX99
Experiment 6 Reporting the Activity Data of This PDC [3]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 1.19 ± 0.06 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

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Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Human papillomavirus-related cervical adenocarcinoma SGC-7901/CPT cell CVCL_0520
Experiment 7 Reporting the Activity Data of This PDC [3]
Indication Colon cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 13.3 ± 1.0 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

   Click to Show/Hide
Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Normal NCM460 cell CVCL_0460
Experiment 8 Reporting the Activity Data of This PDC [3]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 14.9 ± 0.9 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

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Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Normal GES1 cell CVCL_EQ22
Experiment 9 Reporting the Activity Data of This PDC [3]
Indication Liver cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 17.3 ± 0.8 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

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Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Amelanotic melanoma LO #2 cell CVCL_C7SD
Kb-CC02 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 9 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [3]
Indication Colon cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 0.17 ± 0.02 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

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Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Colon carcinoma HCT 116 cell CVCL_0291
Experiment 2 Reporting the Activity Data of This PDC [3]
Indication Colon cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 0.47 ± 0.01 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

   Click to Show/Hide
Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Colon carcinoma HCT-116/CPT cell CVCL_0291
Experiment 3 Reporting the Activity Data of This PDC [3]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 0.50 ± 0.01 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

   Click to Show/Hide
Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Invasive breast carcinoma MCF-7 cell CVCL_0031
Experiment 4 Reporting the Activity Data of This PDC [3]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 0.51 ± 0.03 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

   Click to Show/Hide
Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Gastric carcinoma SGC-7901 cell CVCL_0520
Experiment 5 Reporting the Activity Data of This PDC [3]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 1.23 ± 0.10 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

   Click to Show/Hide
Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Human papillomavirus-related cervical adenocarcinoma SGC-7901/CPT cell CVCL_0520
Experiment 6 Reporting the Activity Data of This PDC [3]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 1.26 ± 0.11 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

   Click to Show/Hide
Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Invasive breast carcinoma of no special type MCF7/C4 cell CVCL_GX99
Experiment 7 Reporting the Activity Data of This PDC [3]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 14.4 ± 0.5 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

   Click to Show/Hide
Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Normal GES1 cell CVCL_EQ22
Experiment 8 Reporting the Activity Data of This PDC [3]
Indication Colon cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 15.4 ± 0.2 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

   Click to Show/Hide
Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Normal NCM460 cell CVCL_0460
Experiment 9 Reporting the Activity Data of This PDC [3]
Indication Liver cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 15.4 ± 0.5 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

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Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Amelanotic melanoma LO #2 cell CVCL_C7SD
Kb-CC01 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 9 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [3]
Indication Colon cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 0.18 ± 0.01 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

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Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Colon carcinoma HCT 116 cell CVCL_0291
Experiment 2 Reporting the Activity Data of This PDC [3]
Indication Colon cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 0.45 ± 0.02 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

   Click to Show/Hide
Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Colon carcinoma HCT-116/CPT cell CVCL_0291
Experiment 3 Reporting the Activity Data of This PDC [3]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 0.57 ± 0.02 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

   Click to Show/Hide
Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Gastric carcinoma SGC-7901 cell CVCL_0520
Experiment 4 Reporting the Activity Data of This PDC [3]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 0.59 ± 0.02 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

   Click to Show/Hide
Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Invasive breast carcinoma MCF-7 cell CVCL_0031
Experiment 5 Reporting the Activity Data of This PDC [3]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 1.34 ± 0.12 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

   Click to Show/Hide
Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Human papillomavirus-related cervical adenocarcinoma SGC-7901/CPT cell CVCL_0520
Experiment 6 Reporting the Activity Data of This PDC [3]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 1.48 ± 0.18 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

   Click to Show/Hide
Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Invasive breast carcinoma of no special type MCF7/C4 cell CVCL_GX99
Experiment 7 Reporting the Activity Data of This PDC [3]
Indication Colon cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 14.0 ± 0.5 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

   Click to Show/Hide
Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Normal NCM460 cell CVCL_0460
Experiment 8 Reporting the Activity Data of This PDC [3]
Indication Liver cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 15.0 ± 0.8 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

   Click to Show/Hide
Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Amelanotic melanoma LO #2 cell CVCL_C7SD
Experiment 9 Reporting the Activity Data of This PDC [3]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 15.5 ± 0.5 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

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Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Normal GES1 cell CVCL_EQ22
Kb-CC06 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 9 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [3]
Indication Colon cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 0.18 ± 0.02 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

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Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Colon carcinoma HCT 116 cell CVCL_0291
Experiment 2 Reporting the Activity Data of This PDC [3]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 0.41 ± 0.02 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

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Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Gastric carcinoma SGC-7901 cell CVCL_0520
Experiment 3 Reporting the Activity Data of This PDC [3]
Indication Colon cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 0.44 ± 0.01 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

   Click to Show/Hide
Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Colon carcinoma HCT-116/CPT cell CVCL_0291
Experiment 4 Reporting the Activity Data of This PDC [3]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 0.51 ± 0.04 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

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Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Invasive breast carcinoma MCF-7 cell CVCL_0031
Experiment 5 Reporting the Activity Data of This PDC [3]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 1.02 ± 0.11 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

   Click to Show/Hide
Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Human papillomavirus-related cervical adenocarcinoma SGC-7901/CPT cell CVCL_0520
Experiment 6 Reporting the Activity Data of This PDC [3]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 1.20 ± 0.13 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

   Click to Show/Hide
Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Invasive breast carcinoma of no special type MCF7/C4 cell CVCL_GX99
Experiment 7 Reporting the Activity Data of This PDC [3]
Indication Colon cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 15.1 ± 0.4 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

   Click to Show/Hide
Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Normal NCM460 cell CVCL_0460
Experiment 8 Reporting the Activity Data of This PDC [3]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 16.0 ± 0.8 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

   Click to Show/Hide
Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Normal GES1 cell CVCL_EQ22
Experiment 9 Reporting the Activity Data of This PDC [3]
Indication Liver cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 16.3 ± 0.4 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

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Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Amelanotic melanoma LO #2 cell CVCL_C7SD
Kb-CC05 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 9 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [3]
Indication Colon cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 0.19 ± 0.02 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

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Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Colon carcinoma HCT 116 cell CVCL_0291
Experiment 2 Reporting the Activity Data of This PDC [3]
Indication Colon cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 0.46 ± 0.02 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

   Click to Show/Hide
Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Colon carcinoma HCT-116/CPT cell CVCL_0291
Experiment 3 Reporting the Activity Data of This PDC [3]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 0.51 ± 0.02 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

   Click to Show/Hide
Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Invasive breast carcinoma MCF-7 cell CVCL_0031
Experiment 4 Reporting the Activity Data of This PDC [3]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 0.54 ± 0.03 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

   Click to Show/Hide
Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Gastric carcinoma SGC-7901 cell CVCL_0520
Experiment 5 Reporting the Activity Data of This PDC [3]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 1.18 ± 0.10 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

   Click to Show/Hide
Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Invasive breast carcinoma of no special type MCF7/C4 cell CVCL_GX99
Experiment 6 Reporting the Activity Data of This PDC [3]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 1.20 ± 0.10 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

   Click to Show/Hide
Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Human papillomavirus-related cervical adenocarcinoma SGC-7901/CPT cell CVCL_0520
Experiment 7 Reporting the Activity Data of This PDC [3]
Indication Liver cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 15.6 ± 0.2 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

   Click to Show/Hide
Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Amelanotic melanoma LO #2 cell CVCL_C7SD
Experiment 8 Reporting the Activity Data of This PDC [3]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 16.0 ± 0.5 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

   Click to Show/Hide
Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Normal GES1 cell CVCL_EQ22
Experiment 9 Reporting the Activity Data of This PDC [3]
Indication Colon cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 16.2 ± 1.0 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is ˜ 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration.

   Click to Show/Hide
Description
MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells.

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In Vitro Model Normal NCM460 cell CVCL_0460
PDC-Z11 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 4 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 0.41 ± 0.13 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 2 Reporting the Activity Data of This PDC [1]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 3.93 ± 1.41 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
Experiment 3 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 10.25 ± 1.34 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Breast adenocarcinoma MDA-MB-231 cell CVCL_0062
Experiment 4 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 12.93 ± 1.15 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Normal MCF-10A cell CVCL_0598
SMAC-P1 CPT conjugates 4 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 5 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [5]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 0.53 ± 0.17 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 2 Reporting the Activity Data of This PDC [5]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 1.58 ± 0.41 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
Experiment 3 Reporting the Activity Data of This PDC [5]
Indication Ovarian cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 2.50 ± 0.78 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Ovarian serous cystadenocarcinoma SK-OV-3 cell CVCL_0532
Experiment 4 Reporting the Activity Data of This PDC [5]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 17.76 ± 1.35 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

   Click to Show/Hide
Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Normal MCF-10A cell CVCL_0598
Experiment 5 Reporting the Activity Data of This PDC [5]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 18.44 ± 2.09 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

   Click to Show/Hide
Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Breast adenocarcinoma MDA-MB-231 cell CVCL_0062
SMAC-P1 CPT conjugates 7 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 5 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [5]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 0.58 ± 0.21 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

   Click to Show/Hide
Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 2 Reporting the Activity Data of This PDC [5]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 3.86 ± 1.84 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

   Click to Show/Hide
Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
Experiment 3 Reporting the Activity Data of This PDC [5]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 4.73 ± 1.55 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Breast adenocarcinoma MDA-MB-231 cell CVCL_0062
Experiment 4 Reporting the Activity Data of This PDC [5]
Indication Ovarian cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 6.17 ± 1.21 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Ovarian serous cystadenocarcinoma SK-OV-3 cell CVCL_0532
Experiment 5 Reporting the Activity Data of This PDC [5]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 15.15 ± 1.44 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Normal MCF-10A cell CVCL_0598
SMAC-P1 CPT conjugates 1 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 5 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [5]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 0.85 ± 0.23 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 2 Reporting the Activity Data of This PDC [5]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 3.04 ± 0.75 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
Experiment 3 Reporting the Activity Data of This PDC [5]
Indication Ovarian cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 4.03 ± 0.25 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Ovarian serous cystadenocarcinoma SK-OV-3 cell CVCL_0532
Experiment 4 Reporting the Activity Data of This PDC [5]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 6.43 ± 1.20 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Breast adenocarcinoma MDA-MB-231 cell CVCL_0062
Experiment 5 Reporting the Activity Data of This PDC [5]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 18.23 ± 2.06 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Normal MCF-10A cell CVCL_0598
PDC-Z4 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 4 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 1.37 ± 0.42 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 2 Reporting the Activity Data of This PDC [1]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 3.45 ± 1.09 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
Experiment 3 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 13.91 ± 2.61 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Breast adenocarcinoma MDA-MB-231 cell CVCL_0062
Experiment 4 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 28.25 ± 3.12 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Normal MCF-10A cell CVCL_0598
PDC-Z5 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 4 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 1.44 ± 0.63 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 2 Reporting the Activity Data of This PDC [1]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 7.83 ± 1.77 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

   Click to Show/Hide
Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
Experiment 3 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 17.84 ± 3.14 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

   Click to Show/Hide
Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Breast adenocarcinoma MDA-MB-231 cell CVCL_0062
Experiment 4 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 20.36 ± 1.82 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

   Click to Show/Hide
Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Normal MCF-10A cell CVCL_0598
I-1 (NPNWGRSWYNQRFKGC=(-SS-O-COO-CPT)GRIKPRKGYTR) [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 5 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [4]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 1.47 ± 0.54 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

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Description
The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 ± 0.54, 3.29 ± 0.67, and 4.29 ± 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 ± 0.07, 1.78 ± 0.47, and 1.27 ± 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 ± 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 ± 1.23 and 7.72 ± 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 ± 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 ± 1.58 and 17.14 ± 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 ± 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation.

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In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 2 Reporting the Activity Data of This PDC [4]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 3.29 ± 0.67 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

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Description
The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 ± 0.54, 3.29 ± 0.67, and 4.29 ± 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 ± 0.07, 1.78 ± 0.47, and 1.27 ± 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 ± 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 ± 1.23 and 7.72 ± 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 ± 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 ± 1.58 and 17.14 ± 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 ± 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation.

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In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
Experiment 3 Reporting the Activity Data of This PDC [4]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 4.29 ± 1.11 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

   Click to Show/Hide
Description
The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 ± 0.54, 3.29 ± 0.67, and 4.29 ± 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 ± 0.07, 1.78 ± 0.47, and 1.27 ± 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 ± 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 ± 1.23 and 7.72 ± 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 ± 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 ± 1.58 and 17.14 ± 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 ± 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation.

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In Vitro Model Ovarian serous cystadenocarcinoma SK-OV-3 cell CVCL_0532
Experiment 4 Reporting the Activity Data of This PDC [4]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 7.60 ± 1.23 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

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Description
The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 ± 0.54, 3.29 ± 0.67, and 4.29 ± 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 ± 0.07, 1.78 ± 0.47, and 1.27 ± 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 ± 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 ± 1.23 and 7.72 ± 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 ± 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 ± 1.58 and 17.14 ± 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 ± 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation.

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In Vitro Model Breast adenocarcinoma MDA-MB-231 cell CVCL_0062
Experiment 5 Reporting the Activity Data of This PDC [4]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 23.90 ± 1.58 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

   Click to Show/Hide
Description
The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 ± 0.54, 3.29 ± 0.67, and 4.29 ± 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 ± 0.07, 1.78 ± 0.47, and 1.27 ± 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 ± 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 ± 1.23 and 7.72 ± 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 ± 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 ± 1.58 and 17.14 ± 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 ± 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation.

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In Vitro Model Normal MCF-10A cell CVCL_0598
I-5 (NPNWGRSWYNQRFKGC=(-SS-COO-CPT)GC=(-SS-COO-CPT)GRIKPRKGYTR) [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 5 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [4]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 1.49 ± 0.58 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

   Click to Show/Hide
Description
The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 ± 0.54, 3.29 ± 0.67, and 4.29 ± 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 ± 0.07, 1.78 ± 0.47, and 1.27 ± 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 ± 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 ± 1.23 and 7.72 ± 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 ± 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 ± 1.58 and 17.14 ± 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 ± 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation.

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In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 2 Reporting the Activity Data of This PDC [4]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 4.12 ± 0.87 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

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Description
The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 ± 0.54, 3.29 ± 0.67, and 4.29 ± 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 ± 0.07, 1.78 ± 0.47, and 1.27 ± 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 ± 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 ± 1.23 and 7.72 ± 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 ± 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 ± 1.58 and 17.14 ± 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 ± 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation.

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In Vitro Model Ovarian serous cystadenocarcinoma SK-OV-3 cell CVCL_0532
Experiment 3 Reporting the Activity Data of This PDC [4]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 7.37 ± 1.18 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

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Description
The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 ± 0.54, 3.29 ± 0.67, and 4.29 ± 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 ± 0.07, 1.78 ± 0.47, and 1.27 ± 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 ± 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 ± 1.23 and 7.72 ± 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 ± 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 ± 1.58 and 17.14 ± 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 ± 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation.

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In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
Experiment 4 Reporting the Activity Data of This PDC [4]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 11.51 ± 1.37 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

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Description
The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 ± 0.54, 3.29 ± 0.67, and 4.29 ± 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 ± 0.07, 1.78 ± 0.47, and 1.27 ± 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 ± 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 ± 1.23 and 7.72 ± 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 ± 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 ± 1.58 and 17.14 ± 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 ± 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation.

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In Vitro Model Breast adenocarcinoma MDA-MB-231 cell CVCL_0062
Experiment 5 Reporting the Activity Data of This PDC [4]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 18.25 ± 1.76 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

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Description
The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 ± 0.54, 3.29 ± 0.67, and 4.29 ± 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 ± 0.07, 1.78 ± 0.47, and 1.27 ± 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 ± 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 ± 1.23 and 7.72 ± 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 ± 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 ± 1.58 and 17.14 ± 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 ± 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation.

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In Vitro Model Normal MCF-10A cell CVCL_0598
PDC-Z12 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 4 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 1.76 ± 0.33 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 2 Reporting the Activity Data of This PDC [1]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 6.12 ± 0.45 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
Experiment 3 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 13.21 ± 1.15 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Breast adenocarcinoma MDA-MB-231 cell CVCL_0062
Experiment 4 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 15.25 ± 2.08 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Normal MCF-10A cell CVCL_0598
SMAC-P1 CPT conjugates 5 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 5 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [5]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 1.78 ± 0.35 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 2 Reporting the Activity Data of This PDC [5]
Indication Ovarian cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 5.81 ± 1.08 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Ovarian serous cystadenocarcinoma SK-OV-3 cell CVCL_0532
Experiment 3 Reporting the Activity Data of This PDC [5]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 6.53 ± 1.02 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
Experiment 4 Reporting the Activity Data of This PDC [5]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 16.24 ± 1.04 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Breast adenocarcinoma MDA-MB-231 cell CVCL_0062
Experiment 5 Reporting the Activity Data of This PDC [5]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 22.12 ± 1.83 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Normal MCF-10A cell CVCL_0598
SMAC-P1 CPT conjugates 8 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 5 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [5]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 2.30 ± 0.48 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 2 Reporting the Activity Data of This PDC [5]
Indication Ovarian cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 4.73 ± 1.33 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Ovarian serous cystadenocarcinoma SK-OV-3 cell CVCL_0532
Experiment 3 Reporting the Activity Data of This PDC [5]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 8.01 ± 1.34 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
Experiment 4 Reporting the Activity Data of This PDC [5]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 15.11 ± 1.80 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Breast adenocarcinoma MDA-MB-231 cell CVCL_0062
Experiment 5 Reporting the Activity Data of This PDC [5]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 28.36 ± 2.12 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Normal MCF-10A cell CVCL_0598
PDC-Z2 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 4 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 2.37 ± 0.32 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 2 Reporting the Activity Data of This PDC [1]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 7.25 ± 1.75 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
Experiment 3 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 19.10 ± 2.94 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Breast adenocarcinoma MDA-MB-231 cell CVCL_0062
Experiment 4 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 24.45 ± 2.04 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Normal MCF-10A cell CVCL_0598
SMAC-P1 CPT conjugates 2 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 5 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [5]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 2.59 ± 0.40 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 2 Reporting the Activity Data of This PDC [5]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 5.93 ± 0.46 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
Experiment 3 Reporting the Activity Data of This PDC [5]
Indication Ovarian cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 8.24 ± 0.57 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Ovarian serous cystadenocarcinoma SK-OV-3 cell CVCL_0532
Experiment 4 Reporting the Activity Data of This PDC [5]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 10.64 ± 1.32 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Breast adenocarcinoma MDA-MB-231 cell CVCL_0062
Experiment 5 Reporting the Activity Data of This PDC [5]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 15.13 ± 1.24 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Normal MCF-10A cell CVCL_0598
PDC-Z3 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 4 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 3.47 ± 0.67 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 2 Reporting the Activity Data of This PDC [1]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 5.51 ± 1.74 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
Experiment 3 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 30.12 ± 1.38 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Normal MCF-10A cell CVCL_0598
Experiment 4 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 32.44 ± 5.49 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Breast adenocarcinoma MDA-MB-231 cell CVCL_0062
PDC-Z10 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 4 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 3.53 ± 0.53 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 2 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 17.25 ± 2.31 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Normal MCF-10A cell CVCL_0598
Experiment 3 Reporting the Activity Data of This PDC [1]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 22.44 ± 2.21 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
Experiment 4 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 25.12 ± 2.04 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Breast adenocarcinoma MDA-MB-231 cell CVCL_0062
PDC-Z1 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 4 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 4.96 ± 0.98 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 2 Reporting the Activity Data of This PDC [1]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 17.94 ± 2.78 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
Experiment 3 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 27.24 ± 1.73 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

   Click to Show/Hide
Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Normal MCF-10A cell CVCL_0598
Experiment 4 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 38.72 ± 4.62 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

   Click to Show/Hide
Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Breast adenocarcinoma MDA-MB-231 cell CVCL_0062
I-2 (NPNWGRSWYNQRFKGC=(-SS-COO-CPT)GRIKPRKGYTR) [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 5 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [4]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 5.76 ± 0.79 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

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Description
The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 ± 0.54, 3.29 ± 0.67, and 4.29 ± 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 ± 0.07, 1.78 ± 0.47, and 1.27 ± 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 ± 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 ± 1.23 and 7.72 ± 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 ± 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 ± 1.58 and 17.14 ± 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 ± 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation.

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In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
Experiment 2 Reporting the Activity Data of This PDC [4]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 6.25 ± 0.96 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

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Description
The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 ± 0.54, 3.29 ± 0.67, and 4.29 ± 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 ± 0.07, 1.78 ± 0.47, and 1.27 ± 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 ± 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 ± 1.23 and 7.72 ± 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 ± 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 ± 1.58 and 17.14 ± 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 ± 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation.

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In Vitro Model Ovarian serous cystadenocarcinoma SK-OV-3 cell CVCL_0532
Experiment 3 Reporting the Activity Data of This PDC [4]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 6.42 ± 1.21 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

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Description
The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 ± 0.54, 3.29 ± 0.67, and 4.29 ± 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 ± 0.07, 1.78 ± 0.47, and 1.27 ± 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 ± 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 ± 1.23 and 7.72 ± 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 ± 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 ± 1.58 and 17.14 ± 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 ± 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation.

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In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 4 Reporting the Activity Data of This PDC [4]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 10.93 ± 1.14 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

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Description
The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 ± 0.54, 3.29 ± 0.67, and 4.29 ± 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 ± 0.07, 1.78 ± 0.47, and 1.27 ± 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 ± 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 ± 1.23 and 7.72 ± 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 ± 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 ± 1.58 and 17.14 ± 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 ± 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation.

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In Vitro Model Breast adenocarcinoma MDA-MB-231 cell CVCL_0062
Experiment 5 Reporting the Activity Data of This PDC [4]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 20.41 ± 1.04 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

   Click to Show/Hide
Description
The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 ± 0.54, 3.29 ± 0.67, and 4.29 ± 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 ± 0.07, 1.78 ± 0.47, and 1.27 ± 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 ± 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 ± 1.23 and 7.72 ± 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 ± 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 ± 1.58 and 17.14 ± 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 ± 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation.

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In Vitro Model Normal MCF-10A cell CVCL_0598
PDC-Z7 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 4 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 5.96 ± 2.41 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 2 Reporting the Activity Data of This PDC [1]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 10.23 ± 1.65 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
Experiment 3 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 15.44 ± 2.41 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Breast adenocarcinoma MDA-MB-231 cell CVCL_0062
Experiment 4 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 33.12 ± 3.84 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

   Click to Show/Hide
Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Normal MCF-10A cell CVCL_0598
I-6 (NPNWGRSWYNQRFKGC=(-S-Maleimide-CPT)GC=(-S-Maleimide-CPT)GRIKPRKGYTR) [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 5 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [4]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 6.72 ± 1.25 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

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Description
The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 ± 0.54, 3.29 ± 0.67, and 4.29 ± 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 ± 0.07, 1.78 ± 0.47, and 1.27 ± 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 ± 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 ± 1.23 and 7.72 ± 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 ± 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 ± 1.58 and 17.14 ± 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 ± 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation.

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In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 2 Reporting the Activity Data of This PDC [4]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 10.91 ± 1.23 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

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Description
The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 ± 0.54, 3.29 ± 0.67, and 4.29 ± 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 ± 0.07, 1.78 ± 0.47, and 1.27 ± 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 ± 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 ± 1.23 and 7.72 ± 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 ± 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 ± 1.58 and 17.14 ± 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 ± 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation.

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In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
Experiment 3 Reporting the Activity Data of This PDC [4]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 20.35 ± 1.21 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

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Description
The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 ± 0.54, 3.29 ± 0.67, and 4.29 ± 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 ± 0.07, 1.78 ± 0.47, and 1.27 ± 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 ± 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 ± 1.23 and 7.72 ± 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 ± 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 ± 1.58 and 17.14 ± 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 ± 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation.

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In Vitro Model Ovarian serous cystadenocarcinoma SK-OV-3 cell CVCL_0532
Experiment 4 Reporting the Activity Data of This PDC [4]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 25.16 ± 2.12 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

   Click to Show/Hide
Description
The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 ± 0.54, 3.29 ± 0.67, and 4.29 ± 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 ± 0.07, 1.78 ± 0.47, and 1.27 ± 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 ± 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 ± 1.23 and 7.72 ± 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 ± 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 ± 1.58 and 17.14 ± 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 ± 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation.

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In Vitro Model Normal MCF-10A cell CVCL_0598
Experiment 5 Reporting the Activity Data of This PDC [4]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 28.24 ± 1.36 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

   Click to Show/Hide
Description
The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 ± 0.54, 3.29 ± 0.67, and 4.29 ± 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 ± 0.07, 1.78 ± 0.47, and 1.27 ± 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 ± 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 ± 1.23 and 7.72 ± 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 ± 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 ± 1.58 and 17.14 ± 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 ± 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation.

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In Vitro Model Breast adenocarcinoma MDA-MB-231 cell CVCL_0062
PDC-Z6 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 4 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 11.02 ± 1.78 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 2 Reporting the Activity Data of This PDC [1]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) > 50 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

   Click to Show/Hide
Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
Experiment 3 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) > 50 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

   Click to Show/Hide
Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Breast adenocarcinoma MDA-MB-231 cell CVCL_0062
Experiment 4 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) > 50 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

   Click to Show/Hide
Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Normal MCF-10A cell CVCL_0598
PDC-Z9 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 4 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 11.63 ± 2.35 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 2 Reporting the Activity Data of This PDC [1]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) > 50 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
Experiment 3 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) > 50 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Breast adenocarcinoma MDA-MB-231 cell CVCL_0062
Experiment 4 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) > 50 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 ± 0.71 M), comparable to that of CPT (IC50 = 2.10 ± 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors.

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Description
To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 ± 0.71 uM) was comparable to that of CPT (IC50 = 2.10 ± 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 ± 0.13 uM) was comparable to that of CPT (IC50 = 0.26 ± 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies.

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In Vitro Model Normal MCF-10A cell CVCL_0598
SMAC-P1 CPT conjugates 9 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 5 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [5]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 12.58 ± 2.45 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 2 Reporting the Activity Data of This PDC [5]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 24.15 ± 3.76 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
Experiment 3 Reporting the Activity Data of This PDC [5]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 31.35 ± 3.17 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Breast adenocarcinoma MDA-MB-231 cell CVCL_0062
Experiment 4 Reporting the Activity Data of This PDC [5]
Indication Ovarian cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) > 50 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Ovarian serous cystadenocarcinoma SK-OV-3 cell CVCL_0532
Experiment 5 Reporting the Activity Data of This PDC [5]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) > 50 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Normal MCF-10A cell CVCL_0598
I-3 (NPNWGRSWYNQRFKGC=(-S-Maleimide-CPT)GRIKPRKGYTR) [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 5 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [4]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 15.32 ± 2.25 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

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Description
The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 ± 0.54, 3.29 ± 0.67, and 4.29 ± 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 ± 0.07, 1.78 ± 0.47, and 1.27 ± 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 ± 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 ± 1.23 and 7.72 ± 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 ± 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 ± 1.58 and 17.14 ± 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 ± 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation.

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In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
Experiment 2 Reporting the Activity Data of This PDC [4]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 23.09 ± 1.77 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

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Description
The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 ± 0.54, 3.29 ± 0.67, and 4.29 ± 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 ± 0.07, 1.78 ± 0.47, and 1.27 ± 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 ± 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 ± 1.23 and 7.72 ± 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 ± 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 ± 1.58 and 17.14 ± 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 ± 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation.

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In Vitro Model Breast adenocarcinoma MDA-MB-231 cell CVCL_0062
Experiment 3 Reporting the Activity Data of This PDC [4]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 24.39 ± 1.45 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

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Description
The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 ± 0.54, 3.29 ± 0.67, and 4.29 ± 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 ± 0.07, 1.78 ± 0.47, and 1.27 ± 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 ± 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 ± 1.23 and 7.72 ± 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 ± 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 ± 1.58 and 17.14 ± 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 ± 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation.

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In Vitro Model Ovarian serous cystadenocarcinoma SK-OV-3 cell CVCL_0532
Experiment 4 Reporting the Activity Data of This PDC [4]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 25.45 ± 0.64 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

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Description
The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 ± 0.54, 3.29 ± 0.67, and 4.29 ± 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 ± 0.07, 1.78 ± 0.47, and 1.27 ± 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 ± 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 ± 1.23 and 7.72 ± 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 ± 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 ± 1.58 and 17.14 ± 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 ± 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation.

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In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 5 Reporting the Activity Data of This PDC [4]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 35.20 ± 2.64 µM
Evaluation Method MTT assay
Administration Time 48 h
MOA of PDC
To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

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Description
The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 ± 0.54, 3.29 ± 0.67, and 4.29 ± 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 ± 0.07, 1.78 ± 0.47, and 1.27 ± 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 ± 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 ± 1.23 and 7.72 ± 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 ± 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 ± 1.58 and 17.14 ± 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 ± 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation.

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In Vitro Model Normal MCF-10A cell CVCL_0598
SMAC-P1 CPT conjugates 6 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 5 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [5]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 15.68 ± 1.14 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 2 Reporting the Activity Data of This PDC [5]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 20.14 ± 2.12 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
Experiment 3 Reporting the Activity Data of This PDC [5]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 28.21 ± 1.28 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Breast adenocarcinoma MDA-MB-231 cell CVCL_0062
Experiment 4 Reporting the Activity Data of This PDC [5]
Indication Ovarian cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) > 50 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Ovarian serous cystadenocarcinoma SK-OV-3 cell CVCL_0532
Experiment 5 Reporting the Activity Data of This PDC [5]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) > 50 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Normal MCF-10A cell CVCL_0598
SMAC-P1 CPT conjugates 3 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 5 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [5]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 18.34 ± 1.42 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 2 Reporting the Activity Data of This PDC [5]
Indication Gastric cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 25.31 ± 1.48 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
Experiment 3 Reporting the Activity Data of This PDC [5]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 30.58 ± 2.76 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Breast adenocarcinoma MDA-MB-231 cell CVCL_0062
Experiment 4 Reporting the Activity Data of This PDC [5]
Indication Ovarian cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) > 50 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Ovarian serous cystadenocarcinoma SK-OV-3 cell CVCL_0532
Experiment 5 Reporting the Activity Data of This PDC [5]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) > 50 µM
Evaluation Method CCK-8 assay
Administration Time 48 h
MOA of PDC
In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

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Description
HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 ± 0.17 uM, 1.58 ± 0.41 uM, 2.50 ± 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 ± 0.11 uM, 2.07 ± 0.67 uM, 4.07 ± 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 ± 2.09 uM and 17.76 ± 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study.

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In Vitro Model Normal MCF-10A cell CVCL_0598
CPT-Cyclo-GCGPep Conjugate 1 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 8 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [204]
Indication Breast cancer
Efficacy Data Cell viability 33.00%
Evaluation Method CCK-8 assay
Administration Time 48 h
Administration Dosage 10 μM
MOA of PDC
In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10-6M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer.

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Description
Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 μM. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 μM and 10 μM. It showed comparable cytotoxicity with CPT at 10 μM. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 μM, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 μM and 2.5 μM. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 μM and 10 μM. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research.

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In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 2 Reporting the Activity Data of This PDC [204]
Indication Gastric tubular adenocarcinoma
Efficacy Data Cell viability 44.00%
Evaluation Method CCK-8 assay
Administration Time 48 h
Administration Dosage 10 μM
MOA of PDC
In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10-6M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer.

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Description
Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 μM. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 μM and 10 μM. It showed comparable cytotoxicity with CPT at 10 μM. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 μM, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 μM and 2.5 μM. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 μM and 10 μM. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research.

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In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
Experiment 3 Reporting the Activity Data of This PDC [204]
Indication Breast cancer
Efficacy Data Cell viability 53.00%
Evaluation Method CCK-8 assay
Administration Time 48 h
Administration Dosage 2.5 μM
MOA of PDC
In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10-6M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer.

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Description
Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 μM. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 μM and 10 μM. It showed comparable cytotoxicity with CPT at 10 μM. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 μM, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 μM and 2.5 μM. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 μM and 10 μM. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research.

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In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 4 Reporting the Activity Data of This PDC [204]
Indication Gastric tubular adenocarcinoma
Efficacy Data Cell viability 53.00%
Evaluation Method CCK-8 assay
Administration Time 48 h
Administration Dosage 2.5 μM
MOA of PDC
In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10-6M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer.

   Click to Show/Hide
Description
Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 μM. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 μM and 10 μM. It showed comparable cytotoxicity with CPT at 10 μM. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 μM, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 μM and 2.5 μM. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 μM and 10 μM. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research.

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In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
Experiment 5 Reporting the Activity Data of This PDC [204]
Indication Breast cancer
Efficacy Data Cell viability 61.00%
Evaluation Method CCK-8 assay
Administration Time 48 h
Administration Dosage 0.625 μM
MOA of PDC
In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10-6M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer.

   Click to Show/Hide
Description
Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 μM. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 μM and 10 μM. It showed comparable cytotoxicity with CPT at 10 μM. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 μM, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 μM and 2.5 μM. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 μM and 10 μM. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research.

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In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 6 Reporting the Activity Data of This PDC [204]
Indication Breast cancer
Efficacy Data Cell viability 76.00%
Evaluation Method CCK-8 assay
Administration Time 48 h
Administration Dosage 0.156 μM
MOA of PDC
In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10-6M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer.

   Click to Show/Hide
Description
Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 μM. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 μM and 10 μM. It showed comparable cytotoxicity with CPT at 10 μM. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 μM, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 μM and 2.5 μM. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 μM and 10 μM. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research.

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In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 7 Reporting the Activity Data of This PDC [204]
Indication Gastric tubular adenocarcinoma
Efficacy Data Cell viability 82.00%
Evaluation Method CCK-8 assay
Administration Time 48 h
Administration Dosage 0.625 μM
MOA of PDC
In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10-6M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer.

   Click to Show/Hide
Description
Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 μM. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 μM and 10 μM. It showed comparable cytotoxicity with CPT at 10 μM. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 μM, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 μM and 2.5 μM. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 μM and 10 μM. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research.

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In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
Experiment 8 Reporting the Activity Data of This PDC [204]
Indication Gastric tubular adenocarcinoma
Efficacy Data Cell viability 85.00%
Evaluation Method CCK-8 assay
Administration Time 48 h
Administration Dosage 0.156 μM
MOA of PDC
In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10-6M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer.

   Click to Show/Hide
Description
Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 μM. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 μM and 10 μM. It showed comparable cytotoxicity with CPT at 10 μM. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 μM, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 μM and 2.5 μM. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 μM and 10 μM. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research.

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In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
PDC-CPT1 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 1 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [205]
Indication Tumor
Efficacy Data Cell viability 38%
Evaluation Method MTT assay
Administration Time 72 h
Administration Dosage 5 µM
Description
Antiproliferative results showed that PTX1 inhibited cell proliferation by 18.7%. The anti-proliferative activity of CPT1 was diminished by 1.9-fold as compared to CPT whereas the activity of CPT2 was comparable to CPT, since CPT2 reduced the cell viability to 61%.
In Vitro Model Invasive breast carcinoma MCF-7 cell CVCL_0031
CPT-Cyclo-GCGPep Conjugate 2 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 8 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [204]
Indication Breast cancer
Efficacy Data Cell viability 45.00%
Evaluation Method CCK-8 assay
Administration Time 48 h
Administration Dosage 10 μM
MOA of PDC
In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10-6M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer.

   Click to Show/Hide
Description
Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 μM. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 μM and 10 μM. It showed comparable cytotoxicity with CPT at 10 μM. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 μM, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 μM and 2.5 μM. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 μM and 10 μM. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research.

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In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 2 Reporting the Activity Data of This PDC [204]
Indication Gastric tubular adenocarcinoma
Efficacy Data Cell viability 45.00%
Evaluation Method CCK-8 assay
Administration Time 48 h
Administration Dosage 10 μM
MOA of PDC
In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10-6M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer.

   Click to Show/Hide
Description
Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 μM. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 μM and 10 μM. It showed comparable cytotoxicity with CPT at 10 μM. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 μM, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 μM and 2.5 μM. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 μM and 10 μM. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research.

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In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
Experiment 3 Reporting the Activity Data of This PDC [204]
Indication Gastric tubular adenocarcinoma
Efficacy Data Cell viability 62.00%
Evaluation Method CCK-8 assay
Administration Time 48 h
Administration Dosage 2.5 μM
MOA of PDC
In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10-6M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer.

   Click to Show/Hide
Description
Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 μM. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 μM and 10 μM. It showed comparable cytotoxicity with CPT at 10 μM. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 μM, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 μM and 2.5 μM. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 μM and 10 μM. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research.

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In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
Experiment 4 Reporting the Activity Data of This PDC [204]
Indication Breast cancer
Efficacy Data Cell viability 69.00%
Evaluation Method CCK-8 assay
Administration Time 48 h
Administration Dosage 2.5 μM
MOA of PDC
In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10-6M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer.

   Click to Show/Hide
Description
Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 μM. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 μM and 10 μM. It showed comparable cytotoxicity with CPT at 10 μM. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 μM, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 μM and 2.5 μM. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 μM and 10 μM. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research.

   Click to Show/Hide
In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 5 Reporting the Activity Data of This PDC [204]
Indication Breast cancer
Efficacy Data Cell viability 78.00%
Evaluation Method CCK-8 assay
Administration Time 48 h
Administration Dosage 0.625 μM
MOA of PDC
In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10-6M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer.

   Click to Show/Hide
Description
Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 μM. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 μM and 10 μM. It showed comparable cytotoxicity with CPT at 10 μM. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 μM, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 μM and 2.5 μM. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 μM and 10 μM. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research.

   Click to Show/Hide
In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 6 Reporting the Activity Data of This PDC [204]
Indication Gastric tubular adenocarcinoma
Efficacy Data Cell viability 80.00%
Evaluation Method CCK-8 assay
Administration Time 48 h
Administration Dosage 0.625 μM
MOA of PDC
In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10-6M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer.

   Click to Show/Hide
Description
Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 μM. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 μM and 10 μM. It showed comparable cytotoxicity with CPT at 10 μM. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 μM, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 μM and 2.5 μM. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 μM and 10 μM. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research.

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In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
Experiment 7 Reporting the Activity Data of This PDC [204]
Indication Breast cancer
Efficacy Data Cell viability 85.00%
Evaluation Method CCK-8 assay
Administration Time 48 h
Administration Dosage 0.156 μM
MOA of PDC
In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10-6M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer.

   Click to Show/Hide
Description
Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 μM. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 μM and 10 μM. It showed comparable cytotoxicity with CPT at 10 μM. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 μM, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 μM and 2.5 μM. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 μM and 10 μM. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research.

   Click to Show/Hide
In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 8 Reporting the Activity Data of This PDC [204]
Indication Gastric tubular adenocarcinoma
Efficacy Data Cell viability 100.00%
Evaluation Method CCK-8 assay
Administration Time 48 h
Administration Dosage 0.156 μM
MOA of PDC
In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10-6M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer.

   Click to Show/Hide
Description
Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 μM. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 μM and 10 μM. It showed comparable cytotoxicity with CPT at 10 μM. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 μM, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 μM and 2.5 μM. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 μM and 10 μM. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research.

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In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
CPT-Cyclo-GCGPep Conjugate 3 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 8 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [204]
Indication Breast cancer
Efficacy Data Cell viability 70.00%
Evaluation Method CCK-8 assay
Administration Time 48 h
Administration Dosage 10 μM
MOA of PDC
In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10-6M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer.

   Click to Show/Hide
Description
Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 μM. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 μM and 10 μM. It showed comparable cytotoxicity with CPT at 10 μM. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 μM, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 μM and 2.5 μM. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 μM and 10 μM. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research.

   Click to Show/Hide
In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 2 Reporting the Activity Data of This PDC [204]
Indication Breast cancer
Efficacy Data Cell viability 90.00%
Evaluation Method CCK-8 assay
Administration Time 48 h
Administration Dosage 2.5 μM
MOA of PDC
In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10-6M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer.

   Click to Show/Hide
Description
Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 μM. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 μM and 10 μM. It showed comparable cytotoxicity with CPT at 10 μM. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 μM, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 μM and 2.5 μM. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 μM and 10 μM. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research.

   Click to Show/Hide
In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 3 Reporting the Activity Data of This PDC [204]
Indication Gastric tubular adenocarcinoma
Efficacy Data Cell viability 90.00%
Evaluation Method CCK-8 assay
Administration Time 48 h
Administration Dosage 10 μM
MOA of PDC
In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10-6M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer.

   Click to Show/Hide
Description
Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 μM. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 μM and 10 μM. It showed comparable cytotoxicity with CPT at 10 μM. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 μM, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 μM and 2.5 μM. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 μM and 10 μM. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research.

   Click to Show/Hide
In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
Experiment 4 Reporting the Activity Data of This PDC [204]
Indication Breast cancer
Efficacy Data Cell viability 98.00%
Evaluation Method CCK-8 assay
Administration Time 48 h
Administration Dosage 0.156 μM
MOA of PDC
In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10-6M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer.

   Click to Show/Hide
Description
Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 μM. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 μM and 10 μM. It showed comparable cytotoxicity with CPT at 10 μM. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 μM, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 μM and 2.5 μM. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 μM and 10 μM. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research.

   Click to Show/Hide
In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 5 Reporting the Activity Data of This PDC [204]
Indication Breast cancer
Efficacy Data Cell viability 99.00%
Evaluation Method CCK-8 assay
Administration Time 48 h
Administration Dosage 0.625 μM
MOA of PDC
In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10-6M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer.

   Click to Show/Hide
Description
Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 μM. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 μM and 10 μM. It showed comparable cytotoxicity with CPT at 10 μM. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 μM, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 μM and 2.5 μM. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 μM and 10 μM. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research.

   Click to Show/Hide
In Vitro Model Breast adenocarcinoma SK-BR-3 cell CVCL_0033
Experiment 6 Reporting the Activity Data of This PDC [204]
Indication Gastric tubular adenocarcinoma
Efficacy Data Cell viability 100.00%
Evaluation Method CCK-8 assay
Administration Time 48 h
Administration Dosage 0.156 μM
MOA of PDC
In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10-6M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer.

   Click to Show/Hide
Description
Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 μM. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 μM and 10 μM. It showed comparable cytotoxicity with CPT at 10 μM. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 μM, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 μM and 2.5 μM. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 μM and 10 μM. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research.

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In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
Experiment 7 Reporting the Activity Data of This PDC [204]
Indication Gastric tubular adenocarcinoma
Efficacy Data Cell viability 100.00%
Evaluation Method CCK-8 assay
Administration Time 48 h
Administration Dosage 0.625 μM
MOA of PDC
In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10-6M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer.

   Click to Show/Hide
Description
Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 μM. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 μM and 10 μM. It showed comparable cytotoxicity with CPT at 10 μM. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 μM, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 μM and 2.5 μM. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 μM and 10 μM. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research.

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In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
Experiment 8 Reporting the Activity Data of This PDC [204]
Indication Gastric tubular adenocarcinoma
Efficacy Data Cell viability 100.00%
Evaluation Method CCK-8 assay
Administration Time 48 h
Administration Dosage 2.5 μM
MOA of PDC
In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10-6M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer.

   Click to Show/Hide
Description
Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 μM. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 μM and 10 μM. It showed comparable cytotoxicity with CPT at 10 μM. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 μM, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 μM and 2.5 μM. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 μM and 10 μM. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research.

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In Vitro Model Gastric tubular adenocarcinoma NCI-N87 cell CVCL_1603
PDC-CPT2 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 1 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [205]
Indication Tumor
Efficacy Data Cell viability 80%
Evaluation Method MTT assay
Administration Time 72 h
Administration Dosage 5 µM
Description
Antiproliferative results showed that PTX1 inhibited cell proliferation by 18.7%. The anti-proliferative activity of CPT1 was diminished by 1.9-fold as compared to CPT whereas the activity of CPT2 was comparable to CPT, since CPT2 reduced the cell viability to 61%.
In Vitro Model Invasive breast carcinoma MCF-7 cell CVCL_0031
CPT-AAM-1 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 5 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [2]
Indication Melanoma
Efficacy Data Cell survival rate 43%
Evaluation Method MTT assay
Administration Time 72 h
Administration Dosage 10 µM
MOA of PDC
In this study, we developed novel melittin analogs with pH-responsive cell-penetrating and membrane-lytic activities by replacing arginines and lysines with histidines. Importantly, we found that the conjugation of cargoes to the N-terminus of melittin analogs decreased their cell-penetrating and membrane-lytic activity compared to the C-terminus, implying that the C-terminus of analogs is more suitable for cargo conjugation. After the attachment of CPT, CPT-AAM-1 and CPT-AAM-2 displayed obvious pH-responsive antitumor activity. CPT-AAM-1 and CPT-AAM-2 destroyed tumor cells through the release of CPT and membrane disruption. Compared with CPT-AAM-2, CPT-AAM-1 showed stronger antitumor activity under acidic conditions. Notably, CPT-AAM-1 significantly inhibited the tumor growth in vivo compared with AAM, AAM-1, and CPT. In addition, CPT-AAM-1 showed relatively low toxicity compared with melittin and CPT. Taken together, our results demonstrate that CPT-AAM-1, with efficient pH-responsive cell-penetrating and membrane-lytic activities, possesses significant therapeutic potential for tumor therapy. This study provides a novel strategy for the development of PDCs based on pH-responsive AMPs for oncology therapeutics.

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Description
Subsequently, the cytotoxicity of these conjugates against B16-F10 cells was determined. As shown in Fig. 4B, CPT-AAM-1 and CPT-AAM-2 displayed significant pH-dependent antitumor activity after 72 h of treatment, whereas the cytotoxicity of CPT showed no obvious difference at pH 7.4 and 5.5. Notably, CPT-AAM-1 and CPT-AAM-2 exhibited greater cytotoxicity than free CPT under acidic conditions, particularly at high concentrations. Compared to CPT-AAM-2, CPT-AAM-1 displayed strong antitumor activity, suggesting that AAM-1 could deliver more CPT molecules into cells. In addition, this result further demonstrates that the C-terminus of AAM is more suitable for drug conjugation than the N-terminus.

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In Vitro Model Mouse melanoma B16-F10 cell CVCL_0159
Experiment 2 Reporting the Activity Data of This PDC [2]
Indication Melanoma
Efficacy Data Cell survival rate 60%
Evaluation Method MTT assay
Administration Time 72 h
Administration Dosage 5 µM
MOA of PDC
In this study, we developed novel melittin analogs with pH-responsive cell-penetrating and membrane-lytic activities by replacing arginines and lysines with histidines. Importantly, we found that the conjugation of cargoes to the N-terminus of melittin analogs decreased their cell-penetrating and membrane-lytic activity compared to the C-terminus, implying that the C-terminus of analogs is more suitable for cargo conjugation. After the attachment of CPT, CPT-AAM-1 and CPT-AAM-2 displayed obvious pH-responsive antitumor activity. CPT-AAM-1 and CPT-AAM-2 destroyed tumor cells through the release of CPT and membrane disruption. Compared with CPT-AAM-2, CPT-AAM-1 showed stronger antitumor activity under acidic conditions. Notably, CPT-AAM-1 significantly inhibited the tumor growth in vivo compared with AAM, AAM-1, and CPT. In addition, CPT-AAM-1 showed relatively low toxicity compared with melittin and CPT. Taken together, our results demonstrate that CPT-AAM-1, with efficient pH-responsive cell-penetrating and membrane-lytic activities, possesses significant therapeutic potential for tumor therapy. This study provides a novel strategy for the development of PDCs based on pH-responsive AMPs for oncology therapeutics.

   Click to Show/Hide
Description
Subsequently, the cytotoxicity of these conjugates against B16-F10 cells was determined. As shown in Fig. 4B, CPT-AAM-1 and CPT-AAM-2 displayed significant pH-dependent antitumor activity after 72 h of treatment, whereas the cytotoxicity of CPT showed no obvious difference at pH 7.4 and 5.5. Notably, CPT-AAM-1 and CPT-AAM-2 exhibited greater cytotoxicity than free CPT under acidic conditions, particularly at high concentrations. Compared to CPT-AAM-2, CPT-AAM-1 displayed strong antitumor activity, suggesting that AAM-1 could deliver more CPT molecules into cells. In addition, this result further demonstrates that the C-terminus of AAM is more suitable for drug conjugation than the N-terminus.

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In Vitro Model Mouse melanoma B16-F10 cell CVCL_0159
Experiment 3 Reporting the Activity Data of This PDC [2]
Indication Melanoma
Efficacy Data Cell survival rate 62%
Evaluation Method MTT assay
Administration Time 72 h
Administration Dosage 2.5 µM
MOA of PDC
In this study, we developed novel melittin analogs with pH-responsive cell-penetrating and membrane-lytic activities by replacing arginines and lysines with histidines. Importantly, we found that the conjugation of cargoes to the N-terminus of melittin analogs decreased their cell-penetrating and membrane-lytic activity compared to the C-terminus, implying that the C-terminus of analogs is more suitable for cargo conjugation. After the attachment of CPT, CPT-AAM-1 and CPT-AAM-2 displayed obvious pH-responsive antitumor activity. CPT-AAM-1 and CPT-AAM-2 destroyed tumor cells through the release of CPT and membrane disruption. Compared with CPT-AAM-2, CPT-AAM-1 showed stronger antitumor activity under acidic conditions. Notably, CPT-AAM-1 significantly inhibited the tumor growth in vivo compared with AAM, AAM-1, and CPT. In addition, CPT-AAM-1 showed relatively low toxicity compared with melittin and CPT. Taken together, our results demonstrate that CPT-AAM-1, with efficient pH-responsive cell-penetrating and membrane-lytic activities, possesses significant therapeutic potential for tumor therapy. This study provides a novel strategy for the development of PDCs based on pH-responsive AMPs for oncology therapeutics.

   Click to Show/Hide
Description
Subsequently, the cytotoxicity of these conjugates against B16-F10 cells was determined. As shown in Fig. 4B, CPT-AAM-1 and CPT-AAM-2 displayed significant pH-dependent antitumor activity after 72 h of treatment, whereas the cytotoxicity of CPT showed no obvious difference at pH 7.4 and 5.5. Notably, CPT-AAM-1 and CPT-AAM-2 exhibited greater cytotoxicity than free CPT under acidic conditions, particularly at high concentrations. Compared to CPT-AAM-2, CPT-AAM-1 displayed strong antitumor activity, suggesting that AAM-1 could deliver more CPT molecules into cells. In addition, this result further demonstrates that the C-terminus of AAM is more suitable for drug conjugation than the N-terminus.

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In Vitro Model Mouse melanoma B16-F10 cell CVCL_0159
Experiment 4 Reporting the Activity Data of This PDC [2]
Indication Melanoma
Efficacy Data Cell survival rate 72%
Evaluation Method MTT assay
Administration Time 72 h
Administration Dosage 1.25 µM
MOA of PDC
In this study, we developed novel melittin analogs with pH-responsive cell-penetrating and membrane-lytic activities by replacing arginines and lysines with histidines. Importantly, we found that the conjugation of cargoes to the N-terminus of melittin analogs decreased their cell-penetrating and membrane-lytic activity compared to the C-terminus, implying that the C-terminus of analogs is more suitable for cargo conjugation. After the attachment of CPT, CPT-AAM-1 and CPT-AAM-2 displayed obvious pH-responsive antitumor activity. CPT-AAM-1 and CPT-AAM-2 destroyed tumor cells through the release of CPT and membrane disruption. Compared with CPT-AAM-2, CPT-AAM-1 showed stronger antitumor activity under acidic conditions. Notably, CPT-AAM-1 significantly inhibited the tumor growth in vivo compared with AAM, AAM-1, and CPT. In addition, CPT-AAM-1 showed relatively low toxicity compared with melittin and CPT. Taken together, our results demonstrate that CPT-AAM-1, with efficient pH-responsive cell-penetrating and membrane-lytic activities, possesses significant therapeutic potential for tumor therapy. This study provides a novel strategy for the development of PDCs based on pH-responsive AMPs for oncology therapeutics.

   Click to Show/Hide
Description
Subsequently, the cytotoxicity of these conjugates against B16-F10 cells was determined. As shown in Fig. 4B, CPT-AAM-1 and CPT-AAM-2 displayed significant pH-dependent antitumor activity after 72 h of treatment, whereas the cytotoxicity of CPT showed no obvious difference at pH 7.4 and 5.5. Notably, CPT-AAM-1 and CPT-AAM-2 exhibited greater cytotoxicity than free CPT under acidic conditions, particularly at high concentrations. Compared to CPT-AAM-2, CPT-AAM-1 displayed strong antitumor activity, suggesting that AAM-1 could deliver more CPT molecules into cells. In addition, this result further demonstrates that the C-terminus of AAM is more suitable for drug conjugation than the N-terminus.

   Click to Show/Hide
In Vitro Model Mouse melanoma B16-F10 cell CVCL_0159
Experiment 5 Reporting the Activity Data of This PDC [2]
Indication Melanoma
Efficacy Data Cell survival rate 88%
Evaluation Method MTT assay
Administration Time 72 h
Administration Dosage 0.625 µM
MOA of PDC
In this study, we developed novel melittin analogs with pH-responsive cell-penetrating and membrane-lytic activities by replacing arginines and lysines with histidines. Importantly, we found that the conjugation of cargoes to the N-terminus of melittin analogs decreased their cell-penetrating and membrane-lytic activity compared to the C-terminus, implying that the C-terminus of analogs is more suitable for cargo conjugation. After the attachment of CPT, CPT-AAM-1 and CPT-AAM-2 displayed obvious pH-responsive antitumor activity. CPT-AAM-1 and CPT-AAM-2 destroyed tumor cells through the release of CPT and membrane disruption. Compared with CPT-AAM-2, CPT-AAM-1 showed stronger antitumor activity under acidic conditions. Notably, CPT-AAM-1 significantly inhibited the tumor growth in vivo compared with AAM, AAM-1, and CPT. In addition, CPT-AAM-1 showed relatively low toxicity compared with melittin and CPT. Taken together, our results demonstrate that CPT-AAM-1, with efficient pH-responsive cell-penetrating and membrane-lytic activities, possesses significant therapeutic potential for tumor therapy. This study provides a novel strategy for the development of PDCs based on pH-responsive AMPs for oncology therapeutics.

   Click to Show/Hide
Description
Subsequently, the cytotoxicity of these conjugates against B16-F10 cells was determined. As shown in Fig. 4B, CPT-AAM-1 and CPT-AAM-2 displayed significant pH-dependent antitumor activity after 72 h of treatment, whereas the cytotoxicity of CPT showed no obvious difference at pH 7.4 and 5.5. Notably, CPT-AAM-1 and CPT-AAM-2 exhibited greater cytotoxicity than free CPT under acidic conditions, particularly at high concentrations. Compared to CPT-AAM-2, CPT-AAM-1 displayed strong antitumor activity, suggesting that AAM-1 could deliver more CPT molecules into cells. In addition, this result further demonstrates that the C-terminus of AAM is more suitable for drug conjugation than the N-terminus.

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In Vitro Model Mouse melanoma B16-F10 cell CVCL_0159
CPT-AAM-2 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 5 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [2]
Indication Melanoma
Efficacy Data Cell survival rate 55%
Evaluation Method MTT assay
Administration Time 72 h
Administration Dosage 10 µM
MOA of PDC
In this study, we developed novel melittin analogs with pH-responsive cell-penetrating and membrane-lytic activities by replacing arginines and lysines with histidines. Importantly, we found that the conjugation of cargoes to the N-terminus of melittin analogs decreased their cell-penetrating and membrane-lytic activity compared to the C-terminus, implying that the C-terminus of analogs is more suitable for cargo conjugation. After the attachment of CPT, CPT-AAM-1 and CPT-AAM-2 displayed obvious pH-responsive antitumor activity. CPT-AAM-1 and CPT-AAM-2 destroyed tumor cells through the release of CPT and membrane disruption. Compared with CPT-AAM-2, CPT-AAM-1 showed stronger antitumor activity under acidic conditions. Notably, CPT-AAM-1 significantly inhibited the tumor growth in vivo compared with AAM, AAM-1, and CPT. In addition, CPT-AAM-1 showed relatively low toxicity compared with melittin and CPT. Taken together, our results demonstrate that CPT-AAM-1, with efficient pH-responsive cell-penetrating and membrane-lytic activities, possesses significant therapeutic potential for tumor therapy. This study provides a novel strategy for the development of PDCs based on pH-responsive AMPs for oncology therapeutics.

   Click to Show/Hide
Description
Subsequently, the cytotoxicity of these conjugates against B16-F10 cells was determined. As shown in Fig. 4B, CPT-AAM-1 and CPT-AAM-2 displayed significant pH-dependent antitumor activity after 72 h of treatment, whereas the cytotoxicity of CPT showed no obvious difference at pH 7.4 and 5.5. Notably, CPT-AAM-1 and CPT-AAM-2 exhibited greater cytotoxicity than free CPT under acidic conditions, particularly at high concentrations. Compared to CPT-AAM-2, CPT-AAM-1 displayed strong antitumor activity, suggesting that AAM-1 could deliver more CPT molecules into cells. In addition, this result further demonstrates that the C-terminus of AAM is more suitable for drug conjugation than the N-terminus.

   Click to Show/Hide
In Vitro Model Mouse melanoma B16-F10 cell CVCL_0159
Experiment 2 Reporting the Activity Data of This PDC [2]
Indication Melanoma
Efficacy Data Cell survival rate 57%
Evaluation Method MTT assay
Administration Time 72 h
Administration Dosage 5 µM
MOA of PDC
In this study, we developed novel melittin analogs with pH-responsive cell-penetrating and membrane-lytic activities by replacing arginines and lysines with histidines. Importantly, we found that the conjugation of cargoes to the N-terminus of melittin analogs decreased their cell-penetrating and membrane-lytic activity compared to the C-terminus, implying that the C-terminus of analogs is more suitable for cargo conjugation. After the attachment of CPT, CPT-AAM-1 and CPT-AAM-2 displayed obvious pH-responsive antitumor activity. CPT-AAM-1 and CPT-AAM-2 destroyed tumor cells through the release of CPT and membrane disruption. Compared with CPT-AAM-2, CPT-AAM-1 showed stronger antitumor activity under acidic conditions. Notably, CPT-AAM-1 significantly inhibited the tumor growth in vivo compared with AAM, AAM-1, and CPT. In addition, CPT-AAM-1 showed relatively low toxicity compared with melittin and CPT. Taken together, our results demonstrate that CPT-AAM-1, with efficient pH-responsive cell-penetrating and membrane-lytic activities, possesses significant therapeutic potential for tumor therapy. This study provides a novel strategy for the development of PDCs based on pH-responsive AMPs for oncology therapeutics.

   Click to Show/Hide
Description
Subsequently, the cytotoxicity of these conjugates against B16-F10 cells was determined. As shown in Fig. 4B, CPT-AAM-1 and CPT-AAM-2 displayed significant pH-dependent antitumor activity after 72 h of treatment, whereas the cytotoxicity of CPT showed no obvious difference at pH 7.4 and 5.5. Notably, CPT-AAM-1 and CPT-AAM-2 exhibited greater cytotoxicity than free CPT under acidic conditions, particularly at high concentrations. Compared to CPT-AAM-2, CPT-AAM-1 displayed strong antitumor activity, suggesting that AAM-1 could deliver more CPT molecules into cells. In addition, this result further demonstrates that the C-terminus of AAM is more suitable for drug conjugation than the N-terminus.

   Click to Show/Hide
In Vitro Model Mouse melanoma B16-F10 cell CVCL_0159
Experiment 3 Reporting the Activity Data of This PDC [2]
Indication Melanoma
Efficacy Data Cell survival rate 74%
Evaluation Method MTT assay
Administration Time 72 h
Administration Dosage 2.5 µM
MOA of PDC
In this study, we developed novel melittin analogs with pH-responsive cell-penetrating and membrane-lytic activities by replacing arginines and lysines with histidines. Importantly, we found that the conjugation of cargoes to the N-terminus of melittin analogs decreased their cell-penetrating and membrane-lytic activity compared to the C-terminus, implying that the C-terminus of analogs is more suitable for cargo conjugation. After the attachment of CPT, CPT-AAM-1 and CPT-AAM-2 displayed obvious pH-responsive antitumor activity. CPT-AAM-1 and CPT-AAM-2 destroyed tumor cells through the release of CPT and membrane disruption. Compared with CPT-AAM-2, CPT-AAM-1 showed stronger antitumor activity under acidic conditions. Notably, CPT-AAM-1 significantly inhibited the tumor growth in vivo compared with AAM, AAM-1, and CPT. In addition, CPT-AAM-1 showed relatively low toxicity compared with melittin and CPT. Taken together, our results demonstrate that CPT-AAM-1, with efficient pH-responsive cell-penetrating and membrane-lytic activities, possesses significant therapeutic potential for tumor therapy. This study provides a novel strategy for the development of PDCs based on pH-responsive AMPs for oncology therapeutics.

   Click to Show/Hide
Description
Subsequently, the cytotoxicity of these conjugates against B16-F10 cells was determined. As shown in Fig. 4B, CPT-AAM-1 and CPT-AAM-2 displayed significant pH-dependent antitumor activity after 72 h of treatment, whereas the cytotoxicity of CPT showed no obvious difference at pH 7.4 and 5.5. Notably, CPT-AAM-1 and CPT-AAM-2 exhibited greater cytotoxicity than free CPT under acidic conditions, particularly at high concentrations. Compared to CPT-AAM-2, CPT-AAM-1 displayed strong antitumor activity, suggesting that AAM-1 could deliver more CPT molecules into cells. In addition, this result further demonstrates that the C-terminus of AAM is more suitable for drug conjugation than the N-terminus.

   Click to Show/Hide
In Vitro Model Mouse melanoma B16-F10 cell CVCL_0159
Experiment 4 Reporting the Activity Data of This PDC [2]
Indication Melanoma
Efficacy Data Cell survival rate 86%
Evaluation Method MTT assay
Administration Time 72 h
Administration Dosage 1.25 µM
MOA of PDC
In this study, we developed novel melittin analogs with pH-responsive cell-penetrating and membrane-lytic activities by replacing arginines and lysines with histidines. Importantly, we found that the conjugation of cargoes to the N-terminus of melittin analogs decreased their cell-penetrating and membrane-lytic activity compared to the C-terminus, implying that the C-terminus of analogs is more suitable for cargo conjugation. After the attachment of CPT, CPT-AAM-1 and CPT-AAM-2 displayed obvious pH-responsive antitumor activity. CPT-AAM-1 and CPT-AAM-2 destroyed tumor cells through the release of CPT and membrane disruption. Compared with CPT-AAM-2, CPT-AAM-1 showed stronger antitumor activity under acidic conditions. Notably, CPT-AAM-1 significantly inhibited the tumor growth in vivo compared with AAM, AAM-1, and CPT. In addition, CPT-AAM-1 showed relatively low toxicity compared with melittin and CPT. Taken together, our results demonstrate that CPT-AAM-1, with efficient pH-responsive cell-penetrating and membrane-lytic activities, possesses significant therapeutic potential for tumor therapy. This study provides a novel strategy for the development of PDCs based on pH-responsive AMPs for oncology therapeutics.

   Click to Show/Hide
Description
Subsequently, the cytotoxicity of these conjugates against B16-F10 cells was determined. As shown in Fig. 4B, CPT-AAM-1 and CPT-AAM-2 displayed significant pH-dependent antitumor activity after 72 h of treatment, whereas the cytotoxicity of CPT showed no obvious difference at pH 7.4 and 5.5. Notably, CPT-AAM-1 and CPT-AAM-2 exhibited greater cytotoxicity than free CPT under acidic conditions, particularly at high concentrations. Compared to CPT-AAM-2, CPT-AAM-1 displayed strong antitumor activity, suggesting that AAM-1 could deliver more CPT molecules into cells. In addition, this result further demonstrates that the C-terminus of AAM is more suitable for drug conjugation than the N-terminus.

   Click to Show/Hide
In Vitro Model Mouse melanoma B16-F10 cell CVCL_0159
Experiment 5 Reporting the Activity Data of This PDC [2]
Indication Melanoma
Efficacy Data Cell survival rate 94%
Evaluation Method MTT assay
Administration Time 72 h
Administration Dosage 0.625 µM
MOA of PDC
In this study, we developed novel melittin analogs with pH-responsive cell-penetrating and membrane-lytic activities by replacing arginines and lysines with histidines. Importantly, we found that the conjugation of cargoes to the N-terminus of melittin analogs decreased their cell-penetrating and membrane-lytic activity compared to the C-terminus, implying that the C-terminus of analogs is more suitable for cargo conjugation. After the attachment of CPT, CPT-AAM-1 and CPT-AAM-2 displayed obvious pH-responsive antitumor activity. CPT-AAM-1 and CPT-AAM-2 destroyed tumor cells through the release of CPT and membrane disruption. Compared with CPT-AAM-2, CPT-AAM-1 showed stronger antitumor activity under acidic conditions. Notably, CPT-AAM-1 significantly inhibited the tumor growth in vivo compared with AAM, AAM-1, and CPT. In addition, CPT-AAM-1 showed relatively low toxicity compared with melittin and CPT. Taken together, our results demonstrate that CPT-AAM-1, with efficient pH-responsive cell-penetrating and membrane-lytic activities, possesses significant therapeutic potential for tumor therapy. This study provides a novel strategy for the development of PDCs based on pH-responsive AMPs for oncology therapeutics.

   Click to Show/Hide
Description
Subsequently, the cytotoxicity of these conjugates against B16-F10 cells was determined. As shown in Fig. 4B, CPT-AAM-1 and CPT-AAM-2 displayed significant pH-dependent antitumor activity after 72 h of treatment, whereas the cytotoxicity of CPT showed no obvious difference at pH 7.4 and 5.5. Notably, CPT-AAM-1 and CPT-AAM-2 exhibited greater cytotoxicity than free CPT under acidic conditions, particularly at high concentrations. Compared to CPT-AAM-2, CPT-AAM-1 displayed strong antitumor activity, suggesting that AAM-1 could deliver more CPT molecules into cells. In addition, this result further demonstrates that the C-terminus of AAM is more suitable for drug conjugation than the N-terminus.

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In Vitro Model Mouse melanoma B16-F10 cell CVCL_0159
References
Ref 1 Discovery of novel HER2 targeting peptide-camptothecin conjugates with effective suppression for selective cancer treatment. Bioorg Chem. 2024 Jun;147:107371. doi: 10.1016/j.bioorg.2024.107371. Epub 2024 Apr 15.
Ref 2 Design of pH-responsive antimicrobial peptide melittin analog-camptothecin conjugates for tumor therapy. Asian J Pharm Sci. 2024 Feb;19(1):100890. doi: 10.1016/j.ajps.2024.100890. Epub 2024 Feb 14.
Ref 3 Design, synthesis and bioactivity investigation of peptide-camptothecin conjugates as anticancer agents with a potential to overcome drug resistance. Int J Pharm. 2023 Oct 15;645:123402. doi: 10.1016/j.ijpharm.2023.123402. Epub 2023 Sep 9.
Ref 4 In Silico Exploration and Biological Evaluation of Bispecific Peptides Derived from Anti-HER2 Antibodies and Peptide-Camptothecin Conjugates for HER2-Positive Breast Cancer. J Med Chem. 2022 Nov 24;65(22):15123-15139. doi: 10.1021/acs.jmedchem.2c00968. Epub 2022 Nov 9.
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