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Published on: September 3, 2013
Discovery of a Potent and Selective GSPT1 Molecular Glue Degrader for the Treatment of Castration-Resistant Prostate
Hui Shen1,2, Hongrui Xu1, Weiqin Jin1,3
1China-New Zealand Joint Laboratory on Biomedicine and Health, State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Biocomputing, Institute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China.
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 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.
Insights
A novel molecular glue, 7d, effectively degrades the cancer driver GSPT1, offering a promising new treatment for castration-resistant prostate cancer (CRPC) by targeting oncogenes.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Castration-resistant prostate cancer (CRPC) treatment faces challenges, driving the need for novel therapeutic strategies.
- Molecular glues offer a new approach by degrading previously untargetable cancer drivers.
- GSPT1 is a key cancer driver implicated in various cancers, including CRPC.
Purpose of the Study:
- To develop a novel CRBN-interacting molecular glue targeting GSPT1.
- To evaluate the efficacy of the developed molecular glue in preclinical models of CRPC.
Main Methods:
- Development of a novel CRBN-interacting molecular glue, designated 7d (XYD049).
- Assessment of GSPT1 degradation efficacy in 22Rv1 cells and comparison with existing compounds.
- Evaluation of 7d's anti-proliferative effects on 22Rv1 cells and in vivo tumor growth inhibition.
- Mechanistic studies to identify downstream targets of GSPT1 degradation.
Main Results:
- 7d potently and selectively degrades GSPT1 in diverse cancer cells, including 22Rv1 cells (DC50 = 19 nM).
- 7d exhibits superior GSPT1 degradation efficacy compared to CC-90009 (compound 1).
- 7d effectively suppresses 22Rv1 cell growth (IC50 = 0.007 ± 0.004 μM) and inhibits tumor growth in mice.
- Degradation of GSPT1 by 7d leads to downregulation of CRPC-related oncogenes (AR, AR-V7, PSA, c-Myc).
Conclusions:
- 7d is a novel, potent, and selective GSPT1 degrader.
- 7d demonstrates significant efficacy in preclinical models of CRPC.
- 7d represents a promising therapeutic strategy for Myc-driven CRPC by targeting GSPT1.
