Molecular Mechanism of Type Ib MET Inhibitors and Their Potential for CNS Tumors

The emergence of targeted therapies for MET exon 14 (METex14) skipping mutations has significantly changed the treatment landscape for NSCLC and other solid tumors. The skipping of METex14 results in activating the MET-HGF pathway and promoting tumor cell proliferation, migration, and preventing apoptosis. Type Ib MET inhibitors, designed to selectively target the "DFG-in" conformation of MET, characteristically bind to the ATP-binding pocket of MET in a U-shaped conformation, extending into the solvent-accessible region and interact strongly with residue Y1230 through π-π interactions, have shown remarkable efficacy in treating METex14-altered NSCLC, including cases with brain metastases (BMs). Notably, vebreltinib and capmatinib have demonstrated superior blood-brain barrier (BBB) permeability in both computational and experimental models, highlighting their potential for treating the central nervous system (CNS) metastases. P-glycoprotein (P-gp) is highly expressed in the BBB, which limits the brain uptake of many highly lipophilic drugs. Despite challenges posed by P-gp mediated efflux, vebreltinib has emerged as a promising candidate for CNS treatment due to its favorable pharmacokinetic profile and minimal susceptibility to P-gp efflux. This study underscores the importance of molecular dynamics simulations in predicting drug efficacy and BBB penetration, providing valuable insights for the development of CNS-targeted metastases therapies.