title: Discovery of small-molecule inhibitors selectively targeting the DNA-binding domain of the human androgen receptor.
abstract: The human androgen receptor (AR) is considered as a master regulator in the development and progression of prostate cancer (PCa). As resistance to clinically used anti-AR drugs remains a major challenge for the treatment of advanced PCa, there is a pressing need for new anti-AR therapeutic avenues. In this study, we identified a binding site on the DNA binding domain (DBD) of the receptor and utilized virtual screening to discover a set of micromolar hits for the target. Through further exploration of the most potent hit (1), a structural analogue (6) was identified demonstrating 10-fold improved anti-AR potency. Further optimization resulted in a more potent synthetic analogue (25) with anti-AR potency comparable to a newly FDA-approved drug Enzalutamide. Site-directed mutagenesis demonstrated that the developed inhibitors do interact with the intended target site. Importantly, the AR DBD inhibitors could effectively inhibit the growth of Enzalutamide-resistant cells as well as block the transcriptional activity of constitutively active AR splice variants, such as V7.
authors: Vancouver Prostate Centre, University of British Columbia , 2660 Oak Street, Vancouver, British Columbia V6H 3Z6, Canada.
authors: Huifang
authors: H
authors: Li
authors: Fuqiang
authors: F
authors: Ban
authors: Kush
authors: K
authors: Dalal
authors: Eric
authors: E
authors: Leblanc
authors: Kate
authors: K
authors: Frewin
authors: Dennis
authors: D
authors: Ma
authors: Hans
authors: H
authors: Adomat
authors: Paul S
authors: PS
authors: Rennie
authors: Artem
authors: A
authors: Cherkasov
mesh_terms: D059002:Androgen Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001549:Benzamides; D001665:Binding Sites; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003198:Computer Simulation; D004247:DNA / Q000378:metabolism*; D062126:Databases, Chemical; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008297:Male; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D009025:Morpholines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D009154:Mutation; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000494:pharmacology; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy; D011774:Pyrvinium Compounds / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014158:Transcription, Genetic
chemical_list: C000594991:4-(4-(4,5-dibromo-1H-imidazol-1-yl)thiazol-2-yl)morpholine; D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents; D001549:Benzamides; D007093:Imidazoles; D009025:Morpholines; D009570:Nitriles; D011774:Pyrvinium Compounds; D011944:Receptors, Androgen; D013844:Thiazoles; D013876:Thiophenes; D010669:Phenylthiohydantoin; C024631:pyrvinium; D004247:DNA; C540278:enzalutamide; D017430:Prostate-Specific Antigen