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Development of Novel Inhibitors Targeting the D-Box of the DNA Binding Domain of Androgen Receptor Radaeva, Mariia; Ban, Fuqiang; Zhang, Fan; LeBlanc, Eric; Lallous, Nada; Rennie, Paul S.; Gleave, Martin E.; Cherkasov, Artem

Abstract

The inhibition of the androgen receptor (AR) is an established strategy in prostate cancer (PCa) treatment until drug resistance develops either through mutations in the ligand-binding domain (LBD) portion of the receptor or its deletion. We previously identified a druggable pocket on the DNA binding domain (DBD) dimerization surface of the AR and reported several potent inhibitors that effectively disrupted DBD-DBD interactions and consequently demonstrated certain antineoplastic activity. Here we describe further development of small molecule inhibitors of AR DBD dimerization and provide their broad biological characterization. The developed compounds demonstrate improved activity in the mammalian two-hybrid assay, enhanced inhibition of AR-V7 transcriptional activity, and improved microsomal stability. These findings position us for the development of AR inhibitors with entirely novel mechanisms of action that would bypass most forms of PCa treatment resistance, including the truncation of the LBD of the AR.

Item Metadata

Title
Development of Novel Inhibitors Targeting the D-Box of the DNA Binding Domain of Androgen Receptor
Creator
Radaeva, Mariia; Ban, Fuqiang; Zhang, Fan; LeBlanc, Eric; Lallous, Nada; Rennie, Paul S.; Gleave, Martin E.; Cherkasov, Artem
Contributor
Vancouver Prostate Centre
Publisher
Multidisciplinary Digital Publishing Institute
Date Issued
2021-03-02
Description
The inhibition of the androgen receptor (AR) is an established strategy in prostate cancer (PCa) treatment until drug resistance develops either through mutations in the ligand-binding domain (LBD) portion of the receptor or its deletion. We previously identified a druggable pocket on the DNA binding domain (DBD) dimerization surface of the AR and reported several potent inhibitors that effectively disrupted DBD-DBD interactions and consequently demonstrated certain antineoplastic activity. Here we describe further development of small molecule inhibitors of AR DBD dimerization and provide their broad biological characterization. The developed compounds demonstrate improved activity in the mammalian two-hybrid assay, enhanced inhibition of AR-V7 transcriptional activity, and improved microsomal stability. These findings position us for the development of AR inhibitors with entirely novel mechanisms of action that would bypass most forms of PCa treatment resistance, including the truncation of the LBD of the AR.
Subject
prostate cancer; computer-aided drug discovery; small-molecule inhibitors; androgen receptor; dimerization
Genre
Article
Type
Text
Language
eng
Date Available
2021-03-12
Provider
Vancouver : University of British Columbia Library
Rights
CC BY 4.0
DOI
10.14288/1.0396114
URI
http://hdl.handle.net/2429/77521
Affiliation
Other UBC
Citation
International Journal of Molecular Sciences 22 (5): 2493 (2021)
Publisher DOI
10.3390/ijms22052493
Peer Review Status
Reviewed
Scholarly Level
Faculty; Researcher
Rights URI
https://creativecommons.org/licenses/by/4.0/
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CC BY 4.0