Peptide-drug Conjugate Information

General Information of This Peptide-drug Conjugate (PDC)
PDC ID
PDC_00057
PDC Name
AEZS-108
Synonyms
Zoptarelin doxorubicin; 139570-93-7; AEZS-108; Zoptarelin doxorubicin [INN]; Zoptarelin doxorubicin [USAN]; AN-152; ZEN-008; 27844X2J29; Lys(6)-LHRH-doxorubicin; Zoptrex; AEZS 108; D-81858; DTXSID50161110; AN152; UNII-27844X2J29; Zoptarelin doxorubicin [USAN:INN]; AN 152; ZOPTARELIN DOXORUBICIN [WHO-DD]; HY-16532; CS-0006380; Q4651377
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PDC Status
Terminated in Phase 3
Indication
In total 2 Indication(s)
Castration and taxane resistant prostate cancer
Uveal melanoma
Structure
Peptide Name
[D-Lys6]-LH-RH
  Peptide Info 
Receptor Name
Gonadotropin-releasing hormone receptor (GNRHR)
  Receptor Info 
Drug Name
Doxorubicin
  Drug Info 
Therapeutic Target
DNA topoisomerase 2-alpha (TOP2A)
  Target Info 
Linker Name
Glutaric acid
  Linker Info 
Peptide Modified Type
Amino acid modifications
Modified Segment
Use D-amino acids instead of L-amino acids
Drugbank ID
DB12755
DrugMap ID
DMAYO46
TTD ID
D02HBB
ChEBI ID
CHEMBL3544954
Formula
C91H117N19O26
#Ro5 Violations (Lipinski): 4 Molecular Weight 1893
Lipid-water partition coefficient (xlogp) -0.4
Hydrogen Bond Donor Count (hbonddonor) 23
Hydrogen Bond Acceptor Count (hbondacc) 29
Rotatable Bond Count (rotbonds) 48
Full List of Activity Data of This Peptide-drug Conjugate
Identified from the Human Clinical Data
Click To Hide/Show 10 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [1]
Indication Castration and taxane resistant prostate cancer
Efficacy Data Alopecia toxicity
52.00%
Description
The most common all-grade adverse events were hematologic (22; 88%), fatigue (19; 76%), anorexia (13; 52%),alopecia(13; 52%), nausea (13; 52%), and vomiting (8;32%).
In Vivo Model Men with histologically confirmed prostatic adenocarcinoma.
Experiment 2 Reporting the Activity Data of This PDC [1]
Indication Castration and taxane resistant prostate cancer
Efficacy Data Fatigue
76%
Description
The most common all-grade adverse events were hematologic (22; 88%), fatigue (19; 76%), anorexia (13; 52%),alopecia(13; 52%), nausea (13; 52%), and vomiting (8;32%).
In Vivo Model Men with histologically confirmed prostatic adenocarcinoma.
Experiment 3 Reporting the Activity Data of This PDC [1]
Indication Castration and taxane resistant prostate cancer
Efficacy Data Grade ≥ 3 hematologic toxicity
56%
Description
Fourteen of 25 patients (56%) experienced a Grade ≥ 3 hematologic toxicity
In Vivo Model Men with histologically confirmed prostatic adenocarcinoma.
Experiment 4 Reporting the Activity Data of This PDC [1]
Indication Castration and taxane resistant prostate cancer
Efficacy Data Grade 3/4 nonhematologic toxicities
24%
Description
Six of 25 patients (24%) experienced Grade 3 or 4 nonhematologic toxicities
In Vivo Model Men with histologically confirmed prostatic adenocarcinoma.
Experiment 5 Reporting the Activity Data of This PDC [1]
Indication Castration and taxane resistant prostate cancer
Efficacy Data Hematologic toxicity
88%
Description
The most common all-grade adverse events were hematologic (22; 88%), fatigue (19; 76%), anorexia (13; 52%),alopecia(13; 52%), nausea (13; 52%), and vomiting (8;32%).
In Vivo Model Men with histologically confirmed prostatic adenocarcinoma.
Experiment 6 Reporting the Activity Data of This PDC [1]
Indication Castration and taxane resistant prostate cancer
Efficacy Data Median overall survival (mOS)
6.0 months
Description
With a median follow-up of 16.1 months (range, 3.2-36.1), the median PFS was 3.8 months (95% confidence interval [CI], 2.1-4.4) and median OS was 6.0 months (95% CI, 4.2-10.1; Figure 3).
In Vivo Model Men with histologically confirmed prostatic adenocarcinoma.
Experiment 7 Reporting the Activity Data of This PDC [1]
Indication Castration and taxane resistant prostate cancer
Efficacy Data Median progression-free survival (mPFS)
3.8 months
Description
With a median follow-up of 16.1 months (range, 3.2-36.1), the median PFS was 3.8 months (95% confidence interval [CI], 2.1-4.4) and median OS was 6.0 months (95% CI, 4.2-10.1; Figure 3).
In Vivo Model Men with histologically confirmed prostatic adenocarcinoma.
Experiment 8 Reporting the Activity Data of This PDC [1]
Indication Castration and taxane resistant prostate cancer
Efficacy Data Nausea toxicity
52%
Description
The most common all-grade adverse events were hematologic (22; 88%), fatigue (19; 76%), anorexia (13; 52%),alopecia(13; 52%), nausea (13; 52%), and vomiting (8;32%).
In Vivo Model Men with histologically confirmed prostatic adenocarcinoma.
Experiment 9 Reporting the Activity Data of This PDC [1]
Indication Castration and taxane resistant prostate cancer
Efficacy Data Neutropenia
56%
Description
The most common hematologic adverse event was neutropenia at 56% (all grades).
In Vivo Model Men with histologically confirmed prostatic adenocarcinoma.
Experiment 10 Reporting the Activity Data of This PDC [1]
Indication Castration and taxane resistant prostate cancer
Efficacy Data Vomit
32%
Description
The most common all-grade adverse events were hematologic (22; 88%), fatigue (19; 76%), anorexia (13; 52%),alopecia(13; 52%), nausea (13; 52%), and vomiting (8;32%).
In Vivo Model Men with histologically confirmed prostatic adenocarcinoma.
Revealed Based on the Cell Line Data
Click To Hide/Show 11 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [2]
Indication Uveal melanoma
Efficacy Data Cell viability
0%
Administration Time 72 h
Administration Dosage 5 µM
Evaluation Method MTT assay
Description
OCM3DOX320cells did not show significant difference in cell viability in the presence of 1 uM DOX when compared to untreated control cells. 1 uM DOX induced significant cell death of OCM3 cells but did not cause significant cell death in OCM3DOX320cells, confirming DOX resistance. AN-152 at lower concentration (40 nM, 320 nM) increased cell proliferation significantly compared to equimolar dose of DOX which does not have any effect on cell viability at this concentration in OCM3 cells. However, higher concentrations of AN-152 can effectively inhibit cell proliferation in both cell lines. Higher concentrations (1-5 uM) of DOX and AN-152 showed no significantly different effect either on OCM3 or OCM3DOX320cells (Fig. 3).

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In Vitro Model Cutaneous melanoma OCM-3 cell CVCL_6937
Half life period 2 h
Experiment 2 Reporting the Activity Data of This PDC [2]
Indication Uveal melanoma
Efficacy Data Cell viability
5%
Administration Time 72 h
Administration Dosage 1 µM
Evaluation Method MTT assay
Description
OCM3DOX320cells did not show significant difference in cell viability in the presence of 1 uM DOX when compared to untreated control cells. 1 uM DOX induced significant cell death of OCM3 cells but did not cause significant cell death in OCM3DOX320cells, confirming DOX resistance. AN-152 at lower concentration (40 nM, 320 nM) increased cell proliferation significantly compared to equimolar dose of DOX which does not have any effect on cell viability at this concentration in OCM3 cells. However, higher concentrations of AN-152 can effectively inhibit cell proliferation in both cell lines. Higher concentrations (1-5 uM) of DOX and AN-152 showed no significantly different effect either on OCM3 or OCM3DOX320cells (Fig. 3).

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In Vitro Model Cutaneous melanoma OCM-3 cell CVCL_6937
Half life period 2 h
Experiment 3 Reporting the Activity Data of This PDC [2]
Indication Uveal melanoma
Efficacy Data Cell viability
6%
Administration Time 72 h
Administration Dosage 2.5 µM
Evaluation Method MTT assay
Description
OCM3DOX320cells did not show significant difference in cell viability in the presence of 1 uM DOX when compared to untreated control cells. 1 uM DOX induced significant cell death of OCM3 cells but did not cause significant cell death in OCM3DOX320cells, confirming DOX resistance. AN-152 at lower concentration (40 nM, 320 nM) increased cell proliferation significantly compared to equimolar dose of DOX which does not have any effect on cell viability at this concentration in OCM3 cells. However, higher concentrations of AN-152 can effectively inhibit cell proliferation in both cell lines. Higher concentrations (1-5 uM) of DOX and AN-152 showed no significantly different effect either on OCM3 or OCM3DOX320cells (Fig. 3).

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In Vitro Model Cutaneous melanoma OCM-3 cell CVCL_6937
Half life period 2 h
Experiment 4 Reporting the Activity Data of This PDC [2]
Indication Uveal melanoma
Efficacy Data Cell viability
25%
Administration Time 72 h
Administration Dosage 5 µM
Evaluation Method MTT assay
Description
OCM3DOX320cells did not show significant difference in cell viability in the presence of 1 uM DOX when compared to untreated control cells. 1 uM DOX induced significant cell death of OCM3 cells but did not cause significant cell death in OCM3DOX320cells, confirming DOX resistance. AN-152 at lower concentration (40 nM, 320 nM) increased cell proliferation significantly compared to equimolar dose of DOX which does not have any effect on cell viability at this concentration in OCM3 cells. However, higher concentrations of AN-152 can effectively inhibit cell proliferation in both cell lines. Higher concentrations (1-5 uM) of DOX and AN-152 showed no significantly different effect either on OCM3 or OCM3DOX320cells (Fig. 3).

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In Vitro Model Cutaneous melanoma OCM3DOX320 cell CVCL_6937
Half life period 2 h
Experiment 5 Reporting the Activity Data of This PDC [3]
Indication Uveal melanoma
Efficacy Data Cell viability
36.30%
Administration Time 24 h
Administration Dosage 5 µM
Evaluation Method MTS assay
MOA of PDC
Our results show that AEZS-108 upregulates the expression of MASPIN/SERPINB5 tumor suppressor gene, which is downregulated in normal uvea and UM specimens independently from the LHRH receptor-ligand interaction. AEZS-108 also substantially downregulates hypoxia-inducible factor 1 alpha (HIF1A) expression.
Description
In order to investigate whether AEZS-108 inhibits cell proliferation and its extent, OCM3 cells were treated either with 5 M AEZS-108 or equal amount of doxorubicin. MTS assay was performed after 24 and 48 hours of treatment. AEZS-108 and doxorubicin have been shown to reduce cell proliferation by 36.3% (p< 0.001) and 62.9% (p< 0.001) respectively after 24 hours, and by 84.7% (p< 0.001) and 89.7% (p< 0.001) respectively after 48 hours, (Figure 2).

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In Vitro Model Cutaneous melanoma OCM-3 cell CVCL_6937
Experiment 6 Reporting the Activity Data of This PDC [2]
Indication Uveal melanoma
Efficacy Data Cell viability
48%
Administration Time 72 h
Administration Dosage 2.5 µM
Evaluation Method MTT assay
Description
OCM3DOX320cells did not show significant difference in cell viability in the presence of 1 uM DOX when compared to untreated control cells. 1 uM DOX induced significant cell death of OCM3 cells but did not cause significant cell death in OCM3DOX320cells, confirming DOX resistance. AN-152 at lower concentration (40 nM, 320 nM) increased cell proliferation significantly compared to equimolar dose of DOX which does not have any effect on cell viability at this concentration in OCM3 cells. However, higher concentrations of AN-152 can effectively inhibit cell proliferation in both cell lines. Higher concentrations (1-5 uM) of DOX and AN-152 showed no significantly different effect either on OCM3 or OCM3DOX320cells (Fig. 3).

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In Vitro Model Cutaneous melanoma OCM3DOX320 cell CVCL_6937
Half life period 2 h
Experiment 7 Reporting the Activity Data of This PDC [2]
Indication Uveal melanoma
Efficacy Data Cell viability
80%
Administration Time 72 h
Administration Dosage 1 µM
Evaluation Method MTT assay
Description
OCM3DOX320cells did not show significant difference in cell viability in the presence of 1 uM DOX when compared to untreated control cells. 1 uM DOX induced significant cell death of OCM3 cells but did not cause significant cell death in OCM3DOX320cells, confirming DOX resistance. AN-152 at lower concentration (40 nM, 320 nM) increased cell proliferation significantly compared to equimolar dose of DOX which does not have any effect on cell viability at this concentration in OCM3 cells. However, higher concentrations of AN-152 can effectively inhibit cell proliferation in both cell lines. Higher concentrations (1-5 uM) of DOX and AN-152 showed no significantly different effect either on OCM3 or OCM3DOX320cells (Fig. 3).

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In Vitro Model Cutaneous melanoma OCM3DOX320 cell CVCL_6937
Half life period 2 h
Experiment 8 Reporting the Activity Data of This PDC [3]
Indication Uveal melanoma
Efficacy Data Cell viability
84.70%
Administration Time 48 h
Administration Dosage 5 µM
Evaluation Method MTS assay
MOA of PDC
Our results show that AEZS-108 upregulates the expression of MASPIN/SERPINB5 tumor suppressor gene, which is downregulated in normal uvea and UM specimens independently from the LHRH receptor-ligand interaction. AEZS-108 also substantially downregulates hypoxia-inducible factor 1 alpha (HIF1A) expression.
Description
In order to investigate whether AEZS-108 inhibits cell proliferation and its extent, OCM3 cells were treated either with 5 M AEZS-108 or equal amount of doxorubicin. MTS assay was performed after 24 and 48 hours of treatment. AEZS-108 and doxorubicin have been shown to reduce cell proliferation by 36.3% (p< 0.001) and 62.9% (p< 0.001) respectively after 24 hours, and by 84.7% (p< 0.001) and 89.7% (p< 0.001) respectively after 48 hours, (Figure 2).

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In Vitro Model Cutaneous melanoma OCM-3 cell CVCL_6937
Experiment 9 Reporting the Activity Data of This PDC [2]
Indication Uveal melanoma
Efficacy Data Cell viability
105%
Administration Time 72 h
Administration Dosage 320 nM
Evaluation Method MTT assay
Description
OCM3DOX320cells did not show significant difference in cell viability in the presence of 1 uM DOX when compared to untreated control cells. 1 uM DOX induced significant cell death of OCM3 cells but did not cause significant cell death in OCM3DOX320cells, confirming DOX resistance. AN-152 at lower concentration (40 nM, 320 nM) increased cell proliferation significantly compared to equimolar dose of DOX which does not have any effect on cell viability at this concentration in OCM3 cells. However, higher concentrations of AN-152 can effectively inhibit cell proliferation in both cell lines. Higher concentrations (1-5 uM) of DOX and AN-152 showed no significantly different effect either on OCM3 or OCM3DOX320cells (Fig. 3).

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In Vitro Model Cutaneous melanoma OCM3DOX320 cell CVCL_6937
Half life period 2 h
Experiment 10 Reporting the Activity Data of This PDC [2]
Indication Uveal melanoma
Efficacy Data Cell viability
120%
Administration Time 72 h
Administration Dosage 40 nM
Evaluation Method MTT assay
Description
OCM3DOX320cells did not show significant difference in cell viability in the presence of 1 uM DOX when compared to untreated control cells. 1 uM DOX induced significant cell death of OCM3 cells but did not cause significant cell death in OCM3DOX320cells, confirming DOX resistance. AN-152 at lower concentration (40 nM, 320 nM) increased cell proliferation significantly compared to equimolar dose of DOX which does not have any effect on cell viability at this concentration in OCM3 cells. However, higher concentrations of AN-152 can effectively inhibit cell proliferation in both cell lines. Higher concentrations (1-5 uM) of DOX and AN-152 showed no significantly different effect either on OCM3 or OCM3DOX320cells (Fig. 3).

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In Vitro Model Cutaneous melanoma OCM3DOX320 cell CVCL_6937
Half life period 2 h
Experiment 11 Reporting the Activity Data of This PDC [2]
Indication Uveal melanoma
Efficacy Data Cell viability
130%
Administration Time 72 h
Administration Dosage 40 nM
Evaluation Method MTT assay
Description
OCM3DOX320cells did not show significant difference in cell viability in the presence of 1 uM DOX when compared to untreated control cells. 1 uM DOX induced significant cell death of OCM3 cells but did not cause significant cell death in OCM3DOX320cells, confirming DOX resistance. AN-152 at lower concentration (40 nM, 320 nM) increased cell proliferation significantly compared to equimolar dose of DOX which does not have any effect on cell viability at this concentration in OCM3 cells. However, higher concentrations of AN-152 can effectively inhibit cell proliferation in both cell lines. Higher concentrations (1-5 uM) of DOX and AN-152 showed no significantly different effect either on OCM3 or OCM3DOX320cells (Fig. 3).

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In Vitro Model Cutaneous melanoma OCM-3 cell CVCL_6937
Half life period 2 h
References
Ref 1 A Phase II Trial of AEZS-108 in Castration- and Taxane-Resistant Prostate Cancer. Clin Genitourin Cancer. 2017 Dec;15(6):742-749. doi: 10.1016/j.clgc.2017.06.002. Epub 2017 Jun 8.
Ref 2 Experimental therapy of doxorubicin resistant human uveal melanoma with targeted cytotoxic luteinizing hormone-releasing hormone analog (AN-152). Eur J Pharm Sci. 2018 Oct 15;123:371-376. doi: 10.1016/j.ejps.2018.08.002. Epub 2018 Aug 2.
Ref 3 The targeted LHRH analog AEZS-108 alters expression of genes related to angiogenesis and development of metastasis in uveal melanoma. Oncotarget. 2020 Jan 14;11(2):175-187. doi: 10.18632/oncotarget.27431. eCollection 2020 Jan 14.