Structural analysis and crystallography-guided pharmacophore elucidation of capmatinib analogues as selective c-MET...

The clinical emergence of class Ib c-MET kinase inhibitors, most prominently represented by the FDA-approved capmatinib, has demonstrated the therapeutic value of selectively targeting aberrant MET signaling in malignancies. Since 2020, several drugs from this class, including capmatinib, savolitinib, glumetinib, and vebreltinib, have achieved regulatory approval worldwide or entered advanced clinical trials. Given the growing clinical importance of class Ib c-MET inhibitors and the structural diversity within this class, this review aims to provide a detailed structural analysis and pharmacophore elucidation of these small molecules based on X-ray crystallographic insights reported over the past two decades (2008-2026). Particular emphasis is placed on characterizing the binding contributions of the distinct structural components of these compounds, including the central nitrogen-containing [5,6]-bicyclic core and the peripheral aromatic substituents A and B, within the c-MET active site. The results of the analyses indicate that the binding pattern is largely dominated by a conserved network of π-mediated interactions, with Met1211 and Tyr1230 acting as crucial interaction nodes defining the general ligand orientation. Concurrently, several key polar (atom-to-atom) contacts contribute to active site anchoring, most notably the conserved hydrogen bond between the backbone -NH- of Asp1222 and a ring nitrogen of the central bicyclic core, together with the hydrogen bond between the backbone -NH- of Met1160 and an acceptor nitrogen within substituent B. Overall, these findings provide a crystallography-based pharmacophoric framework for class Ib c-MET inhibitors and could support the better design of future analogues with improved activity profiles.