2. Academic Validation
  3. Design, synthesis and evaluation of (E)-1-(4-(2-(1H-pyrazol-5-yl)vinyl)phenyl) derivatives as next generation selective RET inhibitors overcoming RET solvent front mutations (G810C/R)

Design, synthesis and evaluation of (E)-1-(4-(2-(1H-pyrazol-5-yl)vinyl)phenyl) derivatives as next generation selective RET inhibitors overcoming RET solvent front mutations (G810C/R)

  • Eur J Med Chem. 2025 Mar 15:286:117294. doi: 10.1016/j.ejmech.2025.117294.
Mingjin Xu 1,  Kaifu Wu 1,  Rui He 2,  Jiahuan He 2,  Gangpeng Yang 3,  Haowen Ma 3,  Lijie Peng 4,  Shuyao Zhang 5,  Li Tan 6,  Zhang Zhang 7,  Qian Cai 8
Affiliations

Affiliations

  • 1 College of Chemistry and Materials Science, Zhejiang Normal University, No. 688 Yingbin Road, Jinhua, Zhejiang Province, 321004, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, School of Pharmacy, Jinan University, Guangzhou, 510632, China.
  • 2 State Key Laboratory of Bioactive Molecules and Druggability Assessment, School of Pharmacy, Jinan University, Guangzhou, 510632, China; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou, 510632, China.
  • 3 College of Chemistry and Materials Science, Zhejiang Normal University, No. 688 Yingbin Road, Jinhua, Zhejiang Province, 321004, China.
  • 4 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou, 510632, China.
  • 5 Department of Pharmacy, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, 510632, China.
  • 6 College of Chemistry and Materials Science, Zhejiang Normal University, No. 688 Yingbin Road, Jinhua, Zhejiang Province, 321004, China. Electronic address: tantanli@zjnu.edu.cn.
  • 7 State Key Laboratory of Bioactive Molecules and Druggability Assessment, School of Pharmacy, Jinan University, Guangzhou, 510632, China; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou, 510632, China; Department of Pharmacy, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, 510632, China. Electronic address: zhang_zhang@jnu.edu.cn.
  • 8 College of Chemistry and Materials Science, Zhejiang Normal University, No. 688 Yingbin Road, Jinhua, Zhejiang Province, 321004, China. Electronic address: caiqian@zjnu.edu.cn.
PMID: 39879936 DOI: 10.1016/j.ejmech.2025.117294
Abstract

RET is a well-recognized drug target for Cancer treatment. Despite the promising efficacy of selective second-generation RET inhibitors Selpercatinib and Pralsetinib, the clinical benefits have been compromised due to the quickly developed resistance to these drugs. RET G810 mutations at the solvent front site have been identified as the major on-target mutations contributing to resistance against Selpercatinib and Pralsetinib. Therefore, there is an urgent need for the development of next-generation RET inhibitors to overcome acquired solvent-front resistance mutations. In this study, a series of (E)-1-(4-(2-(1H-pyrazol-5-yl)vinyl)phenyl) derivatives have been identified as selective next-generation RET inhibitors. The representative compound, CQ1373 exhibits potent cellular potency with IC50 values of 13.0, 25.7 and 28.4 nM against BaF3 cells expressing CCDC6-RET, CCDC6-RET-G810C and CCDC6-RET-G810R, respectively. A comprehensive selectivity profile across 89 kinases reveals that CQ1373 demonstrates good selectivity toward wild-type RET and solvent front mutants G810C/R with IC50 values of 4.2, 7.1 and 32.4 nM, respectively. Furthermore, western blot analysis reveals that CQ1373 effectively inhibits RET phosphorylation and downstream signaling through SHC. It also induces Apoptosis and cell cycle arrest in a dose-dependent manner in BaF3 cells harboring CCDC6-RET, CCDC6-RET-G810C and CCDC6-RET-G810R fusions. More significantly, CQ1373 exhibits promising in vivo anti-tumor efficacy in a CCDC6-RET-G810R mice xenograft model, highlighting its potentials for RET-driven cancers treatment.

Keywords

Kinase; New therapeutic approach; Rearranged during transfection (RET); Selective inhibitors; Solvent front mutations.

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