Selectively targeting the dimerization interface of human androgen receptor with small-molecules to treat castration-resistant prostate cancer

Prostate cancer (PCa) is a leading cause of death for men in North America. The androgen receptor (AR) - a hormone inducible transcription factor - drives expression of tumor promoting genes and represents an important therapeutic target in PCa. The AR is activated by steroid recruitment to its ligand binding domain (LBD), followed by receptor nuclear translocation and dimerization via the DNA binding domain (DBD). Clinically used small molecules interfere with steroid recruitment and prevent AR-driven tumor growth, but are rendered ineffective by emergence of LBD mutations or expression of constitutively active variants, such as ARV7, that lack the LBD. Both drug-resistance mechanisms confound treatment of this 'castration resistant' stage of PCa (CRPC), characterized by return of AR signalling. Here, we employ computer-aided drug-design to develop small molecules that block the AR-DBD dimerization interface, an attractive target given its role in AR activation and independence from the LBD. Virtual screening on the AR-DBD structure led to development of prototypical compounds that block AR dimerization, inhibiting AR-transcriptional activity through a LBD-independent mechanism. Such inhibitors may potentially circumvent AR-dependent resistance mechanisms and directly target CRPC tumor growth.

Cancer letters. 2018 Aug 27 [Epub ahead of print]

Kush Dalal, Fuqiang Ban, Huifang Li, Hélène Morin, Mani Roshan-Moniri, Kevin J Tam, Ashley Shepherd, Aishwariya Sharma, James Peacock, Michael L Carlson, Eric LeBlanc, Carl Perez, Franck Duong, Christopher J Ong, Paul S Rennie, Artem Cherkasov

Vancouver Prostate Centre (VPC), 2660 Oak Street, Vancouver, British Columbia, V6H3Z6, Canada., Department of Biochemistry and Molecular Biology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, V6T 1Z3, Canada., Vancouver Prostate Centre (VPC), 2660 Oak Street, Vancouver, British Columbia, V6H3Z6, Canada. Electronic address: .

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