Details

Autor(en) / Beteiligte

• Orgován, Zoltán
• Péczka, Nikolett
• Petri, László
• Ábrányi-Balogh, Péter
• Ranđelović, Ivan
• Tóth, Szilárd
• Szakács, Gergely
• Nyíri, Kinga
• Vértessy, Beáta
• Pálfy, Gyula
• Vida, István
• Perczel, András
• Tóvári, József
• Keserű, György M.

Titel

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. [Display omitted] •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.