Discovery of a Potent and Selective GSPT1 Molecular Glue Degrader for the Treatment of Castration-Resistant Prostate Cancer

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 DC50 value of 19 nM. It effectively suppresses the growth of 22Rv1 cells with an IC50 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.