Computationally Empowered Workflow Identifies Novel Covalent Allosteric Binders for KRASG12C.

Abstract

Due to its frequent mutations in multiple lethal cancers, KRAS is one of the most‐studied anticancer targets nowadays. Since the discovery of the druggable allosteric binding site containing a G12C mutation, KRASG12C has been the focus of attention in oncology research. We report here a computationally driven approach aimed at identifying novel and selective KRASG12C covalent inhibitors. The workflow involved initial enumeration of virtual molecules tailored for the KRAS allosteric binding site. Tools such as pharmacophore modeling, docking, and free‐energy perturbations were deployed to prioritize the compounds with the best profiles. The synthesized naphthyridinone scaffold showed the ability to react with G12C and inhibit KRASG12C. Analogues were prepared to establish structure‐activity relationships, while molecular dynamics simulations and crystallization of the inhibitor‐KRASG12C complex highlighted an unprecedented binding mode.