Molecular mechanism of type ib MET inhibitors and their potential for CNS tumors.

ABSTRACT: 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) permea

SUBMITTER: Liu Z 

PROVIDER: S-EPMC11865562 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature