Discovery of a Potent and Selective GSPT1 Molecular Glue Degrader for the Treatment of Castration-Resistant Prostate Cancer
Year: 2025
Type: article
Abstract: The treatment of castration-resistant prostate cancer (CRPC) remains a significant challenge, necessitating the development of new and promising therapeutic strategies. Utilizing molecular glue to degrade previously intractable cancer drivers represents an emerging and promising therapeutic approach to cancer treatment. In this study, we developed a novel CRBN-interacting molecular glue, 7d (XYD049), which exhibits potent and selective degradation of G1 to S phase transition 1 (GSPT1), a well-known untargetable cancer driver in diverse cancer cells. Importantly, 7d exhibits superior efficacy compared to 1 (CC-90009) in degrading GSPT1 in 22Rv1 cells with a DC 50 value of 19 nM. It effectively suppresses the growth of 22Rv1 cells with an IC 50 value of 0.007 ± 0.004 μM and demonstrates efficacy in inhibiting 22Rv1 tumor growth in mice. Mechanistically, via degradation of GSPT1, 7d downregulates CRPC-related oncogenes in 22Rv1 cells, including AR, AR-V7, PSA, and c-Myc . Thus, our work provides a novel GSPT1 selective degrader with potent effectiveness in targeting Myc-driven CRPC.
Source: Journal of Medicinal Chemistry
Authors: Hui Shen, Hongrui Xu, Weiqin Jin, Tianbang Wu, Jiankang Hu, Cheng Zhang, Zhixin Zhong, Junhua Li, Rui Mao, Sheng Zhang, Xiao Zhang, Xishan Wu, Jeff B Smaill, Jinxin Xu, Yan Zhang, Yong Xu
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: National Natural Science Foundation of China, Youth Innovation Promotion Association of the Chinese Academy of Sciences, Guangzhou Science and Technology Program key projects, National Key Research and Development Program of China, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Basic and Applied Basic Research Foundation of Guangdong Province
OpenAlex ID: W4406003940