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

J Med Chem. 2011 Dec 22;54(24):8563-73. doi: 10.1021/jm201098n. Epub 2011 Nov 18.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgen Antagonists / chemistry
  • Androgen Antagonists / 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*
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism
  • Small Molecule Libraries*
  • Transcription, Genetic


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