Abstract 7022: Discovery of GLR203701, a highly potent AR PROTAC with favorable PK profile and optimized tissue distribution characteristic

Abstract Prostate cancer is a hormone-dependent tumor, and the androgen receptor (AR) signaling axis drives all stages of prostate cancer, including the lethal, drug-resistant form of the disease termed metastatic castration-resistant prostate cancer (mCRPC). The development of PROTAC targeting AR has become a promising therapeutic strategy to solve the problem of mCRPC drug resistance of prostate cancer. PROTAC drugs generally have both low solubility and permeability, which often lead to poor oral bioavailability and saturated drug absorption, with the systemic exposure reaching a plateau at lower dose. Phase 1 dose escalation trial showed systemic exposure of ARV-766 reached maximum at 320 mg/day in humans. 100 mg/day and 300 mg/day, were selected as the RP2D. The maximum or saturation exposure determines the window in which PROTAC drugs can be ramped up in clinical trials, which is of great significance to the clinical efficacy. Recently, our drug discovery campaign led to the discovery of a potent AR PROTAC, named GLR203701. GLR203701 has good FaSSIF (Fasted State Simulated Intestinal Fluid) solubility, which contributed to a significant improvement of oral bioavailability. Moreover, the maximum exposure of GLR203701 was 5-fold higher than that of ARV-766 in rats and its exposure in beagle dogs reached up to 10-fold higher. In VCaP, LNCaP and 22RV1 cells, GLR203701 could degrade more than 90% of AR, with half-maximal degradation concentration (DC50) < 10 nM. Profound tumor growth inhibition (TGI>90%) was observed in all the three xenograft models, even when the compound was dosed once every other day. GLR203701 was chosen from a STAR (structure-tissue exposure/selectivity-activity relationship) analysis of over 100 pre-screened molecules because of its ideal tissue distribution. GLR203701 had reduced accumulation in liver and kidneys, while achieved 2.7-fold higher exposure in tumor than in plasma. Drug concentration detected in the epididymis and prostate was similar to the blood. Our refined STAR approach has enabled a harmonious balance of drug concentrations among visceral tissues, tumor and disease related organs, benefiting the efficacy/safety. No significant adverse effects were observed when GLR203701 was administered at 120 mg/kg to rats and dogs. Taking the high exposure level and good bioavailability, GLR203701 is expected to generate a board therapeutic window. These preclinical data support the clinical development of GLR203701 for the treatment of mCRPC. Citation Format: Xiaobing Liu, Qianqian Zhao, Yuna Zhang, Yichao Ma, Licong Bu, Kanghua Wang, Weiwei Yu, Fuming Xu, Wenmin Chen. Discovery of GLR203701, a highly potent AR PROTAC with favorable PK profile and optimized tissue distribution characteristic [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 7022.