Discovery of new Lenalidomide derivatives as potent and selective GSPT1 degraders

Yiying Wei; Xinxin Xu; Minchuan Jiang; Yongxing Wang; Yang Zhou; Zhen Wang; Zhang Zhang; Fengtao Zhou; Ke Ding

doi:10.1016/j.ejmech.2023.115580

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. Epub 2023 Jun 19.

Authors

Yiying Wei¹, Xinxin Xu¹, Minchuan Jiang¹, Yongxing Wang², Yang Zhou¹, Zhen Wang¹, Zhang Zhang³, Fengtao Zhou⁴, Ke Ding⁵

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.

MeSH terms

Apoptosis
Lenalidomide / pharmacology
Peptide Termination Factors* / metabolism
Proteasome Endopeptidase Complex
Proteomics*

Substances

Lenalidomide
Peptide Termination Factors
Proteasome Endopeptidase Complex