Abstract
Abstract The clinical development of second-generation androgen receptor (AR) antagonists, including enzalutamide, has confirmed that the AR remains a key oncogene in castration-resistant prostate cancer (CRPC). However, response to enzalutamide is temporary and incremental, and prostate cancer (PCa) cells usually maintain AR expression and signaling upon resistance to AR-targeted therapies. One novel strategy for targeting the AR axis in CRPC is to target proteins through proteasomal degradation, which improves the efficacy and specificity of standard inhibitors. We have developed compounds that bind to AR and engage the proteasomal degradation machinery to specifically degrade the AR protein. Based on this, we hypothesized that the pharmacologic degradation of AR represents an important advance in CRPC treatment, and may provide a novel therapeutic strategy for advanced prostate cancer. These compounds affect AR-positive prostate cancer cells by decreasing AR protein levels as well as disrupting oncogenic AR signaling and enzalutamide resistance. Nanomolar concentrations of AR degraders ultimately lead to decreases in PCa cell growth in vitro and in vivo. In conclusion, we developed highly potent small molecules that induced proteasomal degradation of AR proteins, thus demonstrating degrader compounds to be a potential therapeutic strategy for patients with CRPC. Citation Format: Steven Kregel, Chao Wang, Ester Fernandez-Salas, Kari Wilder-Romans, Xin Han, Chong Qin, Weiguo Xiang, Jean Tien, Xuhong Cao, Corey Speers, Shaomeng Wang, Arul M. Chinnaiyan. Functional and mechanistic interrogation of androgen receptor degraders for the treatment of metastatic castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1001.
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