title: Targeting Binding Function-3 of the Androgen Receptor Blocks Its Co-Chaperone Interactions, Nuclear Translocation, and Activation.
abstract: The development of new antiandrogens, such as enzalutamide, or androgen synthesis inhibitors like abiraterone has improved patient outcomes in the treatment of advanced prostate cancer. However, due to the development of drug resistance and tumor cell survival, a majority of these patients progress to the refractory state of castration-resistant prostate cancer (CRPC). Thus, newer therapeutic agents and a better understanding of their mode of action are needed for treating these CRPC patients. We demonstrated previously that targeting the Binding Function 3 (BF3) pocket of the androgen receptor (AR) has great potential for treating patients with CRPC. Here, we explore the functional activity of this site by using an advanced BF3-specific small molecule (VPC-13566) that was previously reported to effectively inhibit AR transcriptional activity and to displace the BAG1L peptide from the BF3 pocket. We show that VPC-13566 inhibits the growth of various prostate cancer cell lines, including an enzalutamide-resistant cell line, and reduces the growth of AR-dependent prostate cancer xenograft tumors in mice. Importantly, we have used this AR-BF3 binder as a chemical probe and identified a co-chaperone, small glutamine-rich tetratricopeptide repeat (TPR)-containing protein alpha (SGTA), as an important AR-BF3 interacting partner. Furthermore, we used this AR-BF3-directed small molecule to demonstrate that inhibition of AR activity through the BF3 functionality can block translocation of the receptor into the nucleus. These findings suggest that targeting the BF3 site has potential clinical importance, especially in the treatment of CRPC and provide novel insights on the functional role of the BF3 pocket. Mol Cancer Ther; 15(12); 2936-45. ©2016 AACR.
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Nada
authors.initials: N
authors.lastname: Lallous
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Leblanc
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Ravi S N
authors.initials: RS
authors.lastname: Munuganti
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Mohamed D H
authors.initials: MD
authors.lastname: Hassona
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Nader Al
authors.initials: NA
authors.lastname: Nakouzi
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Shannon
authors.initials: S
authors.lastname: Awrey
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Helene
authors.initials: H
authors.lastname: Morin
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Mani
authors.initials: M
authors.lastname: Roshan-Moniri
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Kriti
authors.initials: K
authors.lastname: Singh
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Sam
authors.initials: S
authors.lastname: Lawn
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yamazaki
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Hans H
authors.initials: HH
authors.lastname: Adomat
authors.affiliation: Department of Chemistry, Simon Fraser University, Burnaby, BC, Canada.
authors.forename: Christophe
authors.initials: C
authors.lastname: Andre
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Mads
authors.initials: M
authors.lastname: Daugaard
authors.affiliation: Department of Chemistry, Simon Fraser University, Burnaby, BC, Canada.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Young
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Emma S Tomlinson
authors.initials: ES
authors.lastname: Guns
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Rennie
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada. artc@interchange.ubc.ca.
authors.forename: Artem
authors.initials: A
authors.lastname: Cherkasov
mesh_terms: D059002:Androgen Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides; D014408:Biomarkers, Tumor; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D054730:Protein Interaction Domains and Motifs; D021381:Protein Transport / Q000187:drug effects; D011944:Receptors, Androgen / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D059002:Androgen Receptor Antagonists; D001549:Benzamides; D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D009570:Nitriles; D011944:Receptors, Androgen; D010669:Phenylthiohydantoin; C540278:enzalutamide