Abstract 5678: Novel glucocorticoid receptor degrading bifunctional molecules as therapeutics in castration-resistant prostate cancer

Abstract

Abstract While the majority of men with prostate cancer will experience modest morbidity, advanced castration-resistant prostate cancer (CRPC) remains a devastating disease with significant mortality and limited treatment options. Recently approved anti-androgen therapies such as enzalutamide have shown promising clinical responses. Unfortunately, patients frequently develop resistance to these therapies. Signaling through the glucocorticoid receptor (GR) has emerged as a primary mechanism of resistance to enzalutamide in CRPC suggesting that GR is an attractive therapeutic target. However, existing small molecule antagonists of GR suffer from partial agonist activity leading to activation of a subset of GR target genes which limits their anti-tumor efficacy. To overcome this problem, we have developed bifunctional small molecules or proteolysis targeting chimeras (PROTACs) that induce potent and specific degradation of GR. Using iterative structure-activity relationship (SAR) studies, we have developed a novel chemical linker that imparted superior properties to PROTACs. These novel GR PROTACs induce profound degradation of GR. Using proteomic analysis and quantification of more than 8000 proteins, we show that our GR PROTAC is highly selective for GR. GR PROTACs inhibited proliferation of enzalutamide-resistant prostate cancer cells, have favorable pharmacokinetic properties and are active in vivo. Importantly, GR PROTACs work synergistically with enzalutamide to inhibit growth of prostate cancer xenografts in a castration-resistant mouse model of prostate cancer. Mechanistically, we identified improved suppression of AR and GR target genes in the combination of GR PROTAC and enzalutamide. More importantly, the combination was able to suppress crucial developmental pathways implicated in prostate cancer resistance to therapy and tumor dormancy. Our novel GR PROTACs highlight the power of targeted protein degradation to deliver excellent chemical probes and potentially impactful cancer therapeutics. Citation Format: James T. Link, Nicholas Blazanin, Yonathan Lissanu Deribe. Novel glucocorticoid receptor degrading bifunctional molecules as therapeutics in castration-resistant prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5678.