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, KRAS^G12C has been the focus of attention in oncology research. We report here a computationally driven approach aimed at identifying novel and selective KRAS^G12C 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 KRAS^G12C . Analogues were prepared to establish structure-activity relationships, while molecular dynamics simulations and crystallization of the inhibitor-KRAS^G12C complex highlighted an unprecedented binding mode.

Keywords: KRAS; free-energy perturbation (FEP); medicinal chemistry; molecular dynamics; virtual library design.