Identification and Optimization of Pyridone Derivatives as Pan-MEK/RAF Nondegrading Molecular Glues for the Treatment of RAS-Driven Cancers

  • J Med Chem. 2026 May 28;69(10):12346-12377. doi: 10.1021/acs.jmedchem.6c00242.
Peng Wang  1 ,  Yongting Yuan  1 ,  Linyu Yang  1 ,  Rongrong Sun  1 ,  Weichen Bo  1 ,  Ziyan Ma  1 ,  Songhui Qin  1 ,  Yonglin Chen  1 ,  Mingrui Li  1 ,  Shuai Liu  1 ,  Na Li  1 ,  Zhongning Guo  1 ,  Wei Yan  2 ,  Peng Bai  1 ,  Quan Yuan  1 ,  Taijin Wang  3 ,  Jianhong Yang  1 ,  Mingli Xiang  1 ,  Haoche Wei  4 ,  Jiankun Hu  4 ,  Lijuan Chen  1  3
Affiliations
  • 1. Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 2. Neurology Department, Laboratory of Neuro-System and Multimorbidity, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 3. Chengdu Zenitar Biomedical Technology Co., Ltd., Chengdu 610041, China.
  • 4. Department of General Surgery, Gastric Cancer Center, Laboratory of Gastric Cancer, West China Hospital, Sichuan University, Chengdu 610041, China.
PMID: 42098597 DOI: 10.1021/acs.jmedchem.6c00242
Abstract

In this study, we describe a series of pyridone derivatives as pan-MEK/Raf nondegrading Molecular Glues. Through investigation of the metabolic sites of the reported MEK/Raf Inhibitor 16b, rational design and systematic SAR studies led to the discovery of compound D56, which exhibits well-balanced in vitro and in vivo potency. D56 could effectively block MEK and ERK phosphorylation with IC50 values of 0.379 and 0.015 nM, respectively. Furthermore, protein-protein interaction (PPI) assays demonstrated that D56 induces MEK1-BRAF and MEK1-CRAF complexes formation at low concentrations, indicating that D56 is a potent MEK/Raf molecular glue. D56 possesses an excellent selectivity over Other 332 human-related kinases at 1 μM. Most importantly, in AsPC-1, HCT116, and OCI-AML-3 mouse xenograft models, D56 achieved significant tumor growth inhibition. Taken together, these findings suggest that compound D56 is a potent pan-MEK/Raf nondegrading molecular glue for treating RAS-driven cancers.

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