Targeting the Binding Function 3 (BF3) Site of the Human Androgen Receptor through Virtual Screening.
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- 作者：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
- 刊名：Journal of Medicinal Chemistry
- 出版年：2011
- 出版时间：December 22, 2011
- 年：2011
- 卷：54
- 期：24
- 页码：8563-8573
- 全文大小：523K
- 年卷期：v.54,no.24(December 22, 2011)
- ISSN：1520-4804
文摘
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.