2. Academic Validation
  3. Discovery of a Potent and Selective GSPT1 Molecular Glue Degrader for the Treatment of Castration-Resistant Prostate Cancer

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

  • J Med Chem. 2025 Jan 23;68(2):1553-1571. doi: 10.1021/acs.jmedchem.4c02205.
Hui Shen 1 2,  Hongrui Xu 1,  Weiqin Jin 1 3,  Tianbang Wu 1,  Jiankang Hu 1 2,  Cheng Zhang 1,  Zhixin Zhong 1 2,  Junhua Li 1,  Rui Mao 4,  Sheng Zhang 5,  Xiao Zhang 5,  Xishan Wu 1,  Jeff B Smaill 6 7,  Jinxin Xu 1,  Yan Zhang 1,  Yong Xu 1
Affiliations

Affiliations

  • 1 China-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.
  • 2 University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing 100049, China.
  • 3 Institutes of Material Science and Information Technology, Anhui University, Hefei 230601, China.
  • 4 Laboratory Animal Research Center, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China.
  • 5 Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China.
  • 6 Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
  • 7 Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
PMID: 39746330 DOI: 10.1021/acs.jmedchem.4c02205
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.

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