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

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.

• Authors: 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 54 Issue 24 Pg. 8563-73 (Dec 22 2011) ISSN: 1520-4804 [Electronic] United States
• PMID: 22047606 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Androgen Antagonists
• Ligands
• Receptors, Androgen
• Small Molecule Libraries

Topics

• Androgen Antagonists (chemistry, pharmacology)
• Binding Sites
• Cell Line, Tumor
• Crystallography, X-Ray
• Databases, Factual
• Humans
• Ligands
• Models, Molecular
• Mutation
• Protein Conformation
• Quantitative Structure-Activity Relationship
• Receptors, Androgen (chemistry, genetics, metabolism)
• Small Molecule Libraries
• Transcription, Genetic