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

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.