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De Novo Design of an Androgen Receptor DNA Binding Domain-Targeted peptide PROTAC for Prostate Cancer Therapy
Bohan Ma1, Yizeng Fan1, Dize Zhang1
1Department of Urology, The First Affiliated Hospital, Xi'an Jiaotong University, #277 Yanta West Road, Xi'an, China.
Abstract:
Androgen receptor splice variant-7 (AR-V7), one of the major driving factors, is the most attractive drug target in castration-resistant prostate cancer (CRPC). Currently, no available drugs efficiently target AR-V7 in clinical practice. The DNA binding domain (DBD) is indispensable for the transcriptional activity of AR full length and AR splice variants, including AR-V7. Based on the homodimerization structure of the AR DBD, a novel peptide-based proteolysis-targeting chimera (PROTAC) drug is designed to induce AR and AR-V7 degradation in a DBD and MDM2-dependent manner, without showing any activity on other hormone receptors. To overcome the short half-life and poor cell penetrability of peptide PROTAC drugs, an ultrasmall gold (Au)-peptide complex platform to deliver the AR DBD PROTAC in vivo is developed. The obtained Au-AR pep-PROTAC effectively degrades AR and AR-V7 in prostate cancer cell lines, particularly in CWR22Rv1 cells with DC50 values 48.8 and 79.2 nM, respectively. Au-AR pep-PROTAC results in suppression of AR levels and induces tumor regression in both enzalutamide sensitive and resistant prostate cancer animal models. Further optimization of the Au-AR pep-PROTAC can ultimately lead to a new therapy for AR-V7-positive CRPC.
Insights
A novel gold-peptide PROTAC drug effectively degrades androgen receptor variants, including AR-V7, in prostate cancer models. This approach shows promise for treating castration-resistant prostate cancer, even in drug-resistant cases.
Area of Science:
- Oncology
- Drug Discovery
- Nanotechnology
Background:
- Androgen receptor splice variant-7 (AR-V7) is a key driver in castration-resistant prostate cancer (CRPC).
- Current treatments lack effective AR-V7 targeting agents.
- The DNA binding domain (DBD) is crucial for AR and AR-V7 activity.
Purpose of the Study:
- To design a novel peptide-based proteolysis-targeting chimera (PROTAC) targeting the AR DBD for AR and AR-V7 degradation.
- To develop an ultrasmall gold-peptide complex for enhanced delivery and therapeutic efficacy of the PROTAC drug.
- To evaluate the efficacy of the gold-peptide PROTAC in preclinical prostate cancer models.
Main Methods:
- Design of a peptide PROTAC targeting the AR DBD and utilizing MDM2 for degradation.
- Development of an ultrasmall gold-peptide complex (Au-AR pep-PROTAC) for drug delivery.
- In vitro testing in prostate cancer cell lines and in vivo studies in enzalutamide-sensitive and resistant prostate cancer animal models.
Main Results:
- Au-AR pep-PROTAC demonstrated effective degradation of AR and AR-V7 in prostate cancer cells.
- The complex showed potent activity in CWR22Rv1 cells with low DC50 values.
- In vivo studies showed suppression of AR levels and significant tumor regression in both sensitive and resistant models.
Conclusions:
- The developed Au-AR pep-PROTAC is a promising therapeutic strategy for AR-V7-positive CRPC.
- This approach offers a potential solution for overcoming drug resistance in prostate cancer.
- Further optimization could lead to a novel clinical therapy for advanced prostate cancer.
