Bypassing drug resistance mechanisms of prostate cancer with small molecules that target androgen receptor–chromatin interactions

Kush Dalal, Meixia Che, Nanette S. Que, Aishwariya Sharma, Rendong Yang, Nada Lallous, Hendrik Borgmann, Deniz Ozistanbullu, Ronnie Tse, Fuqiang Ban, Huifang Li, Kevin J. Tam, Mani Roshan-Moniri, Eric LeBlanc, Martin E. Gleave, Daniel T. Gewirth, Scott M. Dehm, Artem Cherkasov, Paul S. Rennie

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Human androgen receptor (AR) is a hormone-activated transcription factor that is an important drug target in the treatment of prostate cancer. Current small-molecule AR antagonists, such as enzalutamide, compete with androgens that bind to the steroid-binding pocket of the AR ligand–binding domain (LBD). In castration-resistant prostate cancer (CRPC), drug resistance can manifest through AR-LBD mutations that convert AR antagonists into agonists, or by expression of AR variants lacking the LBD. Such treatment resistance underscores the importance of novel ways of targeting the AR. Previously, we reported the development of a series of small molecules that were rationally designed to selectively target the AR DNA-binding domain (DBD) and, hence, to directly interfere with AR–DNA interactions. In the current work, we have confirmed that the lead AR DBD inhibitor indeed directly interacts with the AR-DBD and tested that substance across multiple clinically relevant CRPC cell lines. We have also performed a series of experiments that revealed that genome-wide chromatin binding of AR was dramatically impacted by the lead compound (although with lesser effect on AR variants). Collectively, these observations confirm the novel mechanism of antiandrogen action of the developed AR-DBD inhibitors, establishing proof of principle for targeting DBDs of nuclear receptors in endocrine cancers.

Original languageEnglish (US)
Pages (from-to)2281-2291
Number of pages11
JournalMolecular Cancer Therapeutics
Volume16
Issue number10
DOIs
StatePublished - Oct 2017

Bibliographical note

Funding Information:
This work was funded by the Canadian Institutes of Health Research (to P.S. Rennie and A. Cherkasov). The work was also supported by a Prostate Cancer Canada - Translational Acceleration Grant (to P.S. Rennie and A. Cherkasov). The authors acknowledge support from the NIH (grant# R01CA174777; to S.M. Dehm). Financial support was further provided by a Synergistic Idea Development Award from the U.S. Department of Defense (W81XWH-14-1-0518 to S.M. Dehm; W81XWH-14-1-0519 to P.S. Rennie; W81XWH-14-1-0520 to D.T. Gewirth), and additionally the Terry Fox New Frontiers Program Project grant (TFRI project 1062; to P.S. Rennie and A. Cherkasov).

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