Peptide-drug Conjugate Information
General Information of This Peptide-drug Conjugate (PDC)
| PDC ID |
PDC_00222
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| PDC Name |
I-4 (NPNWGRSWYNQRFKGC=(-SS-O-COO-CPT)GC=(-SS-O-COO-CPT)GRIKPRKGYTR)
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| PDC Status |
Investigative
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| Indication |
In total 1 Indication(s)
Breast cancer
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| Structure |
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| Peptide Name |
P1GCGCGT1
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Peptide Info | ||||
| Receptor Name |
Receptor tyrosine-protein kinase erbB-2 (ERBB2)
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Receptor Info | ||||
| Drug Name |
Camptothecin
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Drug Info | ||||
| Therapeutic Target |
DNA topoisomerase 1 (TOP1)
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Target Info | ||||
| Linker Name |
2-(Disulfanyl)ethyl hydrogen carbonate
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Linker Info | ||||
| Formula |
C199H269N57O50S4
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| #Ro5 Violations (Lipinski): 5 | Molecular Weight | 4387.958 | ||||
| Lipid-water partition coefficient (xlogp) | -11.0337 | |||||
| Hydrogen Bond Donor Count (hbonddonor) | 51 | |||||
| Hydrogen Bond Acceptor Count (hbondacc) | 66 | |||||
| Rotatable Bond Count (rotbonds) | 134 | |||||
Full List of Activity Data of This Peptide-drug Conjugate
Revealed Based on the Cell Line Data
| Experiment 1 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | Breast cancer | ||||
| Efficacy Data | Half Maximal Inhibitory Concentration (IC50) |
0.12 ± 0.07 µM
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| Administration Time | 48 h | ||||
| Evaluation Method | MTT assay | ||||
| 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 | [1] | ||||
| Indication | Breast cancer | ||||
| Efficacy Data | Half Maximal Inhibitory Concentration (IC50) |
1.27 ± 0.38 µM
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| Administration Time | 48 h | ||||
| Evaluation Method | MTT assay | ||||
| 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 3 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | Breast cancer | ||||
| Efficacy Data | Half Maximal Inhibitory Concentration (IC50) |
1.78 ± 0.47 µM
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| Administration Time | 48 h | ||||
| Evaluation Method | MTT assay | ||||
| 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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|
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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) |
7.72 ± 0.92 µM
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| Administration Time | 48 h | ||||
| Evaluation Method | MTT assay | ||||
| 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.
Click to Show/Hide
|
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| In Vitro Model | Breast adenocarcinoma | MDA-MB-231 cell | CVCL_0062 | ||
| Experiment 5 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | Breast cancer | ||||
| Efficacy Data | Half Maximal Inhibitory Concentration (IC50) |
17.14 ± 2.42 µM
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| Administration Time | 48 h | ||||
| Evaluation Method | MTT assay | ||||
| 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.
Click to Show/Hide
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| In Vitro Model | Normal | MCF-10A cell | CVCL_0598 | ||
References