2. Academic Validation
  3. Discovery of new Lenalidomide derivatives as potent and selective GSPT1 degraders

Discovery of new Lenalidomide derivatives as potent and selective GSPT1 degraders

  • Eur J Med Chem. 2023 Oct 5;258:115580. doi: 10.1016/j.ejmech.2023.115580.
Yiying Wei 1,  Xinxin Xu 1,  Minchuan Jiang 1,  Yongxing Wang 2,  Yang Zhou 1,  Zhen Wang 1,  Zhang Zhang 3,  Fengtao Zhou 4,  Ke Ding 5
Affiliations

Affiliations

  • 1 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MoE) of the People's Republic of China, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China.
  • 2 Livzon Research Institute, Livzon Pharmaceutical Group Inc., Zhuhai, 519000, China.
  • 3 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MoE) of the People's Republic of China, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China. Electronic address: zhang_zhang@jnu.edu.cn.
  • 4 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MoE) of the People's Republic of China, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China. Electronic address: fengtaozhou@jnu.edu.cn.
  • 5 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MoE) of the People's Republic of China, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China; State Key Laboratory of Bioorganic & Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China. Electronic address: dingk@sioc.ac.cn.
PMID: 37418973 DOI: 10.1016/j.ejmech.2023.115580
Abstract

G1 to S phase transition 1 (GSPT1) is the requisite release factor for the translation termination. GSPT1 is identified as an oncogenic driver of several types of Cancer and considered to be a promising Cancer therapeutic target. Although two selective GSPT1 degraders were advanced into clinical trials, neither of them has been approved for clinical use. Here we developed a series of new selective GSPT1 degraders, among which the optimal compound 9q potently induced degradation of GSPT1 with a DC50 of 35 nM in U937 cells, and showed good selectivity in the global proteomic profiling study. Mechanism studies revealed that compound 9q induced GSPT1 degradation through the ubiquitin-proteasome system. Consistent with its potent GSPT1 degradation activity, compound 9q displayed good antiproliferative activities against U937 cells, MOLT-4 cells, and MV4-11 cells, with IC50 values of 0.019 μM, 0.006 μM, and 0.027 μM, respectively. Compound 9q also dose-dependently induced G0/G1 phase arrest and Apoptosis in U937 cells.

Keywords

Cancer; GSPT1; Molecular glue; Protein degradation.

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