Covalent fragment mapping of KRasG12C revealed novel chemotypes with in vivo potency

G12C mutant KRas is considered druggable by allele-specific covalent inhibitors due to the nucleophilic character of the oncogenic mutant cysteine at position 12. Discovery of these inhibitors requires the optimization of both covalent and noncovalent interactions. Here, we report covalent fragment screening of our elec-trophilic fragment library of diverse non-covalent scaffolds equipped with 40 different electrophilic functionalities to identify fragments as suitable starting points targeting Cys12. Screening the library against KRasG12C using Ellman's free thiol assay, followed by protein NMR and cell viability assays, resulted in two potential inhibitor chemotypes. Characterization of these scaffolds in in vitro cellular-and in vivo xenograft models revealed them as promising starting points for covalent drug discovery programs.

Automated summary

Covalent fragment screening of a diverse library of non-covalent scaffolds equipped with 40 different electrophilic functionalities identified two potential inhibitor chemotypes targeting the G12C mutant KRas. These scaffolds showed promising results in in vitro cellular and in vivo xenograft models, demonstrating their potential as starting points for covalent drug discovery programs.