The development of new anti-androgens such as enzalutamide or androgen synthesis inhibitors like abiraterone have improved patient outcomes in the treatment of advanced prostate cancer (PCa). However, due to the development of drug resistance and tumor cell survival, the 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 PCa cell lines including an enzalutamide-resistant cell line and reduces the growth of AR-dependant PCa 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 employed 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.
- Received June 2, 2016.
- Revision received August 16, 2016.
- Accepted September 4, 2016.
- Copyright ©2016, American Association for Cancer Research.