Targeting the binding function 3 (BF3) site of the human androgen receptor through virtual screening.

Nathan A Lack, Peter Axerio-Cilies, Peyman Tavassoli, Frank Q Han, Ka Hong Chan, Clementine Feau, Eric LeBlanc, Emma Tomlinson Guns, R Kiplin Guy, Paul S Rennie, Artem Cherkasov

Index: J. Med. Chem. 54 , 8563-73, (2011)

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Abstract

The androgen receptor (AR) is the best studied drug target for the treatment of prostate cancer. While there are a number of drugs that target the AR, they all work through the same mechanism of action and are prone to the development of drug resistance. There is a large unmet need for novel AR inhibitors which work through alternative mechanism(s). Recent studies have identified a novel site on the AR called binding function 3 (BF3) that is involved into AR transcriptional activity. In order to identify inhibitors that target the BF3 site, we have conducted a large-scale in silico screen followed by experimental evaluation. A number of compounds were identified that effectively inhibited the AR transcriptional activity with no obvious cytotoxicity. The mechanism of action of these compounds was validated by biochemical assays and X-ray crystallography. These findings lay a foundation for the development of alternative or supplementary therapies capable of combating prostate cancer even in its antiandrogen resistant forms.