Novel Inhibitors of androgen receptor's DNA binding domain identified using an ultra-large virtual screening
Mariia Radaeva1, Helene Morin1, Mohit Pandey1
1Vancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, British Columbia, Canada, V6H 3Z6.
Abstract:
Androgen receptor (AR) inhibition remains the primary strategy to combat the progression of prostate cancer (PC). However, all clinically used AR inhibitors target the ligand-binding domain (LBD), which is highly susceptible to truncations through splicing or mutations that confer drug resistance. Thus, there exists an urgent need for AR inhibitors with novel modes of action. We thus launched a virtual screening of an ultra-large chemical library to find novel inhibitors of the AR DNA-binding domain (DBD) at two sites: protein-DNA interface (P-box) and dimerization site (D-box). The compounds selected through vigorous computational filtering were then experimentally validated. We identified several novel chemotypes that effectively suppress transcriptional activity of AR and its splice variant V7. The identified compounds represent previously unexplored chemical scaffolds with a mechanism of action that evades the conventional drug resistance manifested through LBD mutations. Additionally, we describe the binding features required to inhibit AR DBD at both P-box and D-box target sites.
Insights
New androgen receptor (AR) inhibitors targeting the DNA-binding domain (DBD) offer a novel strategy against prostate cancer (PC). These compounds overcome resistance mechanisms associated with current ligand-binding domain (LBD) inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Androgen receptor (AR) inhibition is a cornerstone treatment for prostate cancer (PC).
- Current AR inhibitors target the ligand-binding domain (LBD), leading to acquired drug resistance via mutations or splice variants like AR-V7.
- Novel therapeutic strategies targeting alternative AR domains are urgently needed.
Purpose of the Study:
- To identify novel inhibitors targeting the AR DNA-binding domain (DBD).
- To explore new chemical scaffolds that circumvent resistance mechanisms associated with LBD inhibitors.
- To characterize the binding modes for inhibiting AR DBD at the P-box and D-box.
Main Methods:
- Virtual screening of an ultra-large chemical library against AR DBD target sites (P-box and D-box).
- Computational filtering and rigorous selection of potential inhibitor candidates.
- Experimental validation of computationally identified compounds for AR transcriptional activity suppression.
Main Results:
- Identification of novel chemotypes inhibiting AR transcriptional activity.
- Demonstrated efficacy against both full-length AR and the resistant splice variant AR-V7.
- Compounds exhibit a mechanism of action distinct from LBD-targeting drugs, bypassing common resistance pathways.
Conclusions:
- Novel AR DBD inhibitors represent a promising new class of therapeutics for prostate cancer.
- These compounds effectively suppress AR signaling and overcome LBD-associated drug resistance.
- Targeting the AR DBD offers a viable strategy to combat treatment-resistant prostate cancer.
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