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Covalent fragment mapping of KRasG12C revealed novel chemotypes with in vivo potency
Ist Teil von
European journal of medicinal chemistry, 2023-03, Vol.250, p.115212-115212, Article 115212
Ort / Verlag
Elsevier Masson SAS
Erscheinungsjahr
2023
Quelle
Alma/SFX Local Collection
Beschreibungen/Notizen
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 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.
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•Novel screening cascade was used to identify covalent fragments targeting KRASG12C.•585 compounds with 40 different electrophilic functionalities were screened.•Two compounds demonstrated promising cellular and in vivo efficacy.•CFL-120 showed comparable in vivo efficacy to the prototype inhibitor ARS-1620.
Sprache
Englisch
Identifikatoren
ISSN: 0223-5234
eISSN: 1768-3254
DOI: 10.1016/j.ejmech.2023.115212
Titel-ID: cdi_proquest_miscellaneous_2780488282
Format
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