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

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.