Abstract 396: Discovery of SHR3591, a highly potent and orally bioavailable AR PROTAC for the treatment of prostate cancer

Abstract Prostate cancer is the second most common cancer in men after lung cancer. Androgen receptor (AR) signaling plays a key role in the development and progression of prostate cancer. A number of AR-centered therapies have been developed for the treatment of prostate cancer, such as CYP17A1 inhibitor abiraterone, which blocks the androgen synthesis pathway, and a series of second-generation AR antagonists. Unfortunately, resistance mechanisms to these AR-signaling targeted agents usually develop within 18 months of treatment, including AR amplification, various ligand-binding domain (LBD) mutations and splicing variants. However, AR signaling still plays an important role in these resistant settings. Therefore, it’s urgent to develop new therapeutic strategies targeting AR, particularly for the treatment of metastatic castration-resistant prostate cancer (mCRPC). To meet this challenge, proteolysis-targeting chimera (PROTAC) technology provides a possible solution. We disclose herein SHR3591 as an orally bioavailable AR PROTAC for the treatment of prostate cancer, which is potent in degrading both AR wildtype and LBD mutations.SHR3591 demonstrated nanomolar AR degradation activities in both LNCaP (DC50: 7.9 nM) and AR-amplified VCaP cells (DC50: 7.5 nM). To our delight, SHR3591 also degraded various clinically relevant AR mutants, including H875Y, T878A, W742L, F877L and M896V with single-digit nanomolar potency. One of the most common mutant L702H could also be degraded efficiently with a DC50 value less than 20 nM. Meanwhile, no obvious degradation of neosubstrates of common CRBN binders, such as IKZF1, IKZF3 or GSPT1, were observed (DC50>10000 nM), displaying good selectivity. The in vivo PD experiment was carried out in castrated male mice harboring VCaP tumors with 10 mg/kg of SHR3591 treatment (po, qd×3). Over 90% of AR proteins were degraded by SHR3591 treatment. Furthermore, in a VCaP xenograft model, SHR3591 showed robust anti-tumor activity in a dose-dependent manner, leading to tumor regression (TGI > 130%) at as low as 3 mg/kg (po, qd), without obvious influences in mouse body weight during 25 days of treatment. Additionally, SHR3591 also displayed favorable pharmacokinetic profiles across preclinical species with oral bioavailability more than 20%. In conclusion, SHR3591 has been developed as a highly potent and orally bioavailable AR PROTAC, exhibiting superior AR degradation activities and good selectivity in vitro. SHR3591 could efficiently degrade AR WT and clinically relevant mutants including L702H. Furthermore, SHR3591 displayed excellent PD effect and robust tumor inhibition activity in vivo. SHR3591 showed favorable pharmacokinetic profiles across different preclinical species as well. SHR3591 has advanced into phase1/1b clinical studies in patients with mCRPC. Citation Format: Minqiang Jia, Limin Zhang, Fanglong Yang, Gang Chen, Shouli Zhao, Weimin Wang, Jiangtao Chi, Wei Peng, Luona Wang, Huishuang Miao, Zhibin Xu, Yuchang Mao, Xun Li, Yi Mao, Shuyu Cai, Jun Feng, Min Hu, Xin Li, Feng He. Discovery of SHR3591, a highly potent and orally bioavailable AR PROTAC for the treatment of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 396.