AI Article Synopsis
- The G12C mutant KRas is deemed druggable with specific inhibitors due to a reactive cysteine residue at position 12.
- Researchers screened an extensive library of electrophilic fragments with various non-covalent structures to find potential inhibitors targeting this specific cysteine.
- Two promising inhibitor chemotypes were identified through assays and further characterized in both lab and animal models, demonstrating potential for future drug development.
Article Abstract
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 electrophilic 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 KRas 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.
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| http://dx.doi.org/10.1016/j.ejmech.2023.115212 | DOI Listing |
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