Abstract 1805: Development of a selective androgen receptor degrader (SARD) for treatment of castration-resistant prostate cancer

Abstract

Abstract Current treatments for prostate cancer are centered on blocking androgen-signaling axis, which is the target of several clinical androgen receptor (AR) antagonists such as enzalutamide. Recent studies have shown that a single AR mutation (F876L) converts enzalutamide from an antagonist to an agonist—a fate shared by earlier antagonists as well such as bicalutamide and flutamide. While hormonal therapy is often successful in the initial stages of the disease, prostatic tumors inevitably become resistant to these therapeutics. Remarkably though, several mechanistic studies suggest that the androgen receptor signaling remains active even in these hormonal refractory cancers, which suggests that AR remains a viable target in the castration-resistant prostate cancers (CRPC). Thus, novel therapeutics that target and degrade AR could provide unique druggable opportunities for complete and more sustained AR inhibition in prostate cancers. Based on an AR-gelsolin interaction in a mammalian two-hybrid luciferase assay, we conducted a screen of an in-house library of 170,000 compounds, re-assayed and validated the top 2K hits. The top 500 hits were then characterized in a battery of assays such as AR-driven gene expression, inhibition of cell proliferation in WT and mutant cell lines, ChIP-seq, transcriptional and conformational profiling, and AR degradation studies. We have identified a selective androgen receptor degrader (SARD) series that shows efficacy against both WT and AR mutants. Further structure-activity relationship (SAR) studies revealed analogs with IC50 equivalent or superior to enzalutamide. In vivo studies are currently under way to evaluate the efficacy of the optimized lead in mouse tumor xenografts. These preclinical findings highlight the utility of SARDs as an effective therapeutic prostate tumor strategy in the context of AR mutations and overexpression that bestow resistance to the second-generation AR antagonists. Citation Format: ZhongKe Yao, Suzanne Wardell, Ivan Spasojevic, John Norris, John Katzenellenbogen, Donald McDonnell, Jatinder S. Josan. Development of a selective androgen receptor degrader (SARD) for treatment of castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1805.