Targeting Binding Function-3 of the Androgen Receptor Blocks Its Co-Chaperone Interactions, Nuclear Translocation, and Activation.

Autor:	Lallous N; Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada., Leblanc E; Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada., Munuganti RS; Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada., Hassona MD; Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada., Nakouzi NA; Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada., Awrey S; Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada., Morin H; Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada., Roshan-Moniri M; Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada., Singh K; Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada., Lawn S; Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada., Yamazaki T; Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada., Adomat HH; Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada., Andre C; Department of Chemistry, Simon Fraser University, Burnaby, BC, Canada., Daugaard M; Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada., Young RN; Department of Chemistry, Simon Fraser University, Burnaby, BC, Canada., Guns ES; Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada., Rennie PS; Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada., Cherkasov A; Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada. artc@interchange.ubc.ca.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2016 Dec; Vol. 15 (12), pp. 2936-2945. Date of Electronic Publication: 2016 Oct 07.
DOI:	10.1158/1535-7163.MCT-16-0354
Abstrakt:	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. Competing Interests: The authors disclose no potential conflicts of interest. (©2016 American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu