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: Nada Lallous, Eric Leblanc, Ravi S N Munuganti, Mohamed D H Hassona, Nader Al Nakouzi, Shannon Awrey, Helene Morin, Mani Roshan-Moniri, Kriti Singh, Sam Lawn, Takeshi Yamazaki, Hans H Adomat, Christophe Andre, Mads Daugaard, Robert N Young, Emma S Tomlinson Guns, Paul S Rennie, Artem Cherkasov
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 15 Issue 12 Pg. 2936-2945 (12 2016) ISSN: 1538-8514 [Electronic] United States
• PMID: 27765852 (Publication Type: Journal Article)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Androgen Receptor Antagonists
• Benzamides
• Biomarkers, Tumor
• Carrier Proteins
• Nitriles
• Receptors, Androgen
• Phenylthiohydantoin
• enzalutamide

Topics

• Androgen Receptor Antagonists (chemistry, pharmacology)
• Animals
• Benzamides
• Biomarkers, Tumor
• Carrier Proteins (metabolism)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Male
• Mice
• Molecular Conformation
• Molecular Docking Simulation
• Molecular Dynamics Simulation
• Nitriles
• Phenylthiohydantoin (analogs & derivatives, pharmacology)
• Prostatic Neoplasms (drug therapy, genetics, metabolism, pathology)
• Protein Binding (drug effects)
• Protein Interaction Domains and Motifs
• Protein Transport (drug effects)
• Receptors, Androgen (chemistry, metabolism)
• Signal Transduction (drug effects)
• Transcription, Genetic (drug effects)
• Xenograft Model Antitumor Assays