Abstract 2508: The development of anti-androgens with a novel mechanism of action for treatment of castration-resistant prostate cancer
Authors: Munuganti Ravi Shashi Nayana , Hassona Mohamed DH , Leblanc Eric , Ban Fuqiang , Guns Emma T. , Rennie Paul S. , Cherkasov Artem 
Published: May 2015

Abstract
The androgen receptor (AR) is one of the most validated therapeutic targets in prostate cancer (PCa). Conventional anti-androgens lose effectiveness as cancer therapeutics because anti-androgen resistance usually develops after long term treatment. The challenge is that the current therapeutics bind to the same site of the AR (hormone binding pocket) and act via the same mode, to which the receptor has already developed effective resistance mechanisms. Hence, there is a pressing need for novel therapeutics that inhibit the AR through novel, alternative modes of action. Recent studies have identified a novel binding pocket on the surface of AR called binding function 3 (BF3) that is important for the AR transcriptional activity. In order to identify compounds that specifically bind to BF3 site and inhibit the AR, we conducted a systematic in silico screen (that included large-scale docking, in-site rescoring, and consensus voting procedures) followed by experimental validation of the identified hit molecules. As a result, we have discovered a novel chemical series of indoles as lead BF3 inhibitors. One of the most potent inhibitors identified, VPC-13163, demonstrated an IC50 of 0.31µM in AR eGFP transcriptional assay. Confirming it as a true BF3 binder, VPC-13163 neither displaced the co-activator from an alternative coactivator binding site, activation function 2 site, nor androgen from the hormone binding pocket. Additionally, the Biolayer Interferometry assay detected direct reversible interactions between the AR ligand binding domain and the inhibitor. VPC-13163 demonstrated strong anti-proliferative activity against LNCaP and Enzalutamide-resistant prostate cancer cell lines (MR49F) whereas it did not affect the growth of AR independent PC3 cell line. It also inhibits prostate specific antigen (PSA) in both LNCaP and MR49F and reduces expression of AR target genes, PSA and TMPRSS2. These findings suggest that VPC-13163 exhibits AR BF3 specific mechanism of action. Furthermore, VPC-13163 reduces AR-dependent growth of xenograft tumors in vivo. Based on these outcomes, it can be anticipated that such drug prototypes will lay a foundation for the development of alternative or supplementary small-molecule therapies capable of combating PCa even in its drug resistant forms. Because the emergence of castration resistance is the lethal end stage of the disease, we anticipate that the proposed research will eventually have a substantial impact on patient survival.
Citation Format: Ravi Shashi Nayana Munuganti, Mohamed DH Hassona, Eric Leblanc, Fuqiang Ban, Emma T. Guns, Paul S. Rennie, Artem Cherkasov. The development of anti-androgens with a novel mechanism of action for treatment of castration-resistant prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2508. doi:10.1158/1538-7445.AM2014-2508