title: Identification of novel androgen receptor antagonists using structure- and ligand-based methods.
abstract: Androgen receptor (AR) plays a critical role in the development and progression of prostate cancer (PCa). The AR hormone-binding site (HBS) is intensively studied and represents the target area for current antiandrogens including Bicalutamide and structurally related Enzalutamide. As resistance to antiandrogens invariably emerges in advanced prostate cancer, there exists a high medical need for the identification and development of novel AR antagonists of different chemotypes. Given the wealth of structural information on the AR in complex with a variety of ligands, we have applied an integrated structure- and ligand-based virtual screening methodology to identify novel AR antagonists. Virtual hits generated by a consensus voting approach were experimentally evaluated and resulted in the discovery of a number of structurally diverse submicromolar antagonists of the AR. In particular, one identified compound demonstrated anti-AR potency in vitro that is comparable to the clinically used Bicalutamide. These results set a ground for the development of novel classes of PCa drugs that are structurally different from current AR antagonists.
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, British Columbia V6H 3Z6, Canada. hli@prostatecentre.com
authors.forename: Huifang
authors.initials: H
authors.lastname: Li
authors.forename: Xin
authors.initials: X
authors.lastname: Ren
authors.forename: Eric
authors.initials: E
authors.lastname: Leblanc
authors.forename: Kate
authors.initials: K
authors.lastname: Frewin
authors.forename: Paul S
authors.initials: PS
authors.lastname: Rennie
authors.forename: Artem
authors.initials: A
authors.lastname: Cherkasov
mesh_terms: D059002:Androgen Receptor Antagonists / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000728:Androgens / Q000378:metabolism; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D017430:Prostate-Specific Antigen / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D011944:Receptors, Androgen / Q000737:chemistry / Q000378:metabolism*; D014584:User-Computer Interface
chemical_list: D059002:Androgen Receptor Antagonists; D000728:Androgens; D008024:Ligands; D011944:Receptors, Androgen; D017430:Prostate-Specific Antigen