title: 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: Vancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, British Columbia V6H 3Z6, Canada.
authors: Nathan A
authors: NA
authors: Lack
authors: Peter
authors: P
authors: Axerio-Cilies
authors: Peyman
authors: P
authors: Tavassoli
authors: Frank Q
authors: FQ
authors: Han
authors: Ka Hong
authors: KH
authors: Chan
authors: Clementine
authors: C
authors: Feau
authors: Eric
authors: E
authors: LeBlanc
authors: Emma Tomlinson
authors: ET
authors: Guns
authors: R Kiplin
authors: RK
authors: Guy
authors: Paul S
authors: PS
authors: Rennie
authors: Artem
authors: A
authors: Cherkasov
mesh_terms: D000726:Androgen Antagonists / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D016208:Databases, Factual; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D011944:Receptors, Androgen / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D054852:Small Molecule Libraries; D014158:Transcription, Genetic
chemical_list: D000726:Androgen Antagonists; D008024:Ligands; D011944:Receptors, Androgen; D054852:Small Molecule Libraries