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Open AccessArticle

Targeting Alternative Sites on the Androgen Receptor to Treat Castration-Resistant Prostate Cancer

Vancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada
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Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2013, 14(6), 12496-12519; https://doi.org/10.3390/ijms140612496
Received: 3 May 2013 / Revised: 29 May 2013 / Accepted: 3 June 2013 / Published: 14 June 2013
(This article belongs to the Special Issue Molecular Research in Urology)
Recurrent, metastatic prostate cancer continues to be a leading cause of cancer-death in men. The androgen receptor (AR) is a modular, ligand-inducible transcription factor that regulates the expression of genes that can drive the progression of this disease, and as a consequence, this receptor is a key therapeutic target for controlling prostate cancer. The current drugs designed to directly inhibit the AR are called anti-androgens, and all act by competing with androgens for binding to the androgen/ligand binding site. Unfortunately, with the inevitable progression of the cancer to castration resistance, many of these drugs become ineffective. However, there are numerous other regulatory sites on this protein that have not been exploited therapeutically. The regulation of AR activity involves a cascade of complex interactions with numerous chaperones, co-factors and co-regulatory proteins, leading ultimately to direct binding of AR dimers to specific DNA androgen response elements within the promoter and enhancers of androgen-regulated genes. As part of the family of nuclear receptors, the AR is organized into modular structural and functional domains with specialized roles in facilitating their inter-molecular interactions. These regions of the AR present attractive, yet largely unexploited, drug target sites for reducing or eliminating androgen signaling in prostate cancers. The design of small molecule inhibitors targeting these specific AR domains is only now being realized and is the culmination of decades of work, including crystallographic and biochemistry approaches to map the shape and accessibility of the AR surfaces and cavities. Here, we review the structure of the AR protein and describe recent advancements in inhibiting its activity with small molecules specifically designed to target areas distinct from the receptor’s androgen binding site. It is anticipated that these new classes of anti-AR drugs will provide an additional arsenal to treat castration-resistant prostate cancer. View Full-Text
Keywords: androgen receptor; prostate cancer; castration resistance; anti-androgens; protein structure; structure-based drug design androgen receptor; prostate cancer; castration resistance; anti-androgens; protein structure; structure-based drug design
MDPI and ACS Style

Lallous, N.; Dalal, K.; Cherkasov, A.; Rennie, P.S. Targeting Alternative Sites on the Androgen Receptor to Treat Castration-Resistant Prostate Cancer. Int. J. Mol. Sci. 2013, 14, 12496-12519. https://doi.org/10.3390/ijms140612496

AMA Style

Lallous N, Dalal K, Cherkasov A, Rennie PS. Targeting Alternative Sites on the Androgen Receptor to Treat Castration-Resistant Prostate Cancer. International Journal of Molecular Sciences. 2013; 14(6):12496-12519. https://doi.org/10.3390/ijms140612496

Chicago/Turabian Style

Lallous, Nada; Dalal, Kush; Cherkasov, Artem; Rennie, Paul S. 2013. "Targeting Alternative Sites on the Androgen Receptor to Treat Castration-Resistant Prostate Cancer" Int. J. Mol. Sci. 14, no. 6: 12496-12519. https://doi.org/10.3390/ijms140612496

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