Current treatments for prostate cancer are centered on blocking androgen-signaling axis, which is the target of several clinical AR antagonists, including enzalutamide. Recent studies have shown that a single AR mutation (F876L) converts enzalutamide from an antagonist to an agonist – a fate shared with earlier antagonists such as bicalutamide and flutamide.  Thus, while hormonal therapy is often initially successful, prostate tumors inevitably become resistant. Remarkably though, several mechanistic studies suggest that AR remains a viable target in these hormone refractory cancers. Thus, novel therapeutics that target and degrade AR could provide unique druggable opportunities for complete and sustained AR inhibition in prostate cancers. Based on an AR-gelsolin interaction screen of an in-house library of 170,000 compounds, and further follow-up of top hits with AR-driven gene expression, inhibition of VCaP cell proliferation, transcriptional and conformational profiling, and AR degradation studies, we have identified a Selective Androgen Receptor Degrader (SARD) that shows efficacy against both WT and AR mutants. Further structure-activity relationship (SAR) revealed analogs with IC<sub>50</sub> equivalent or superior to enzalutamide. In vivo studies are currently underway to evaluate efficacy in mouse tumor xenografts. These preclinical findings highlight the utility of SARDs as effective therapeutic prostate tumor strategy in the context of AR overexpression and mutations that confer resistance to second-generation AR antagonists.<br/>

Discovery of a selective androgen receptor degrader (SARD) for treatment of castration-resistant prostate cancer

254th National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.