2. Academic Validation
  3. Covalent fragment mapping of KRasG12C revealed novel chemotypes with in vivo potency

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

  • Eur J Med Chem. 2023 Mar 15;250:115212. doi: 10.1016/j.ejmech.2023.115212.
Zoltán Orgován 1,  Nikolett Péczka 2,  László Petri 1,  Péter Ábrányi-Balogh 2,  Ivan Ranđelović 3,  Szilárd Tóth 4,  Gergely Szakács 4,  Kinga Nyíri 5,  Beáta Vértessy 5,  Gyula Pálfy 6,  István Vida 6,  András Perczel 6,  József Tóvári 7,  György M Keserű 8
Affiliations

Affiliations

  • 1 Medicinal Chemistry Research Group, Research Centre for Natural Sciences, and National Drug Discovery and Development Laboratory, Budapest, Hungary.
  • 2 Medicinal Chemistry Research Group, Research Centre for Natural Sciences, and National Drug Discovery and Development Laboratory, Budapest, Hungary; Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Budapest, Hungary.
  • 3 KINETO Lab Ltd, Budapest, Hungary.
  • 4 Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary.
  • 5 Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary; Department of Applied Biotechnology and Food Science, Budapest University of Technology and Economics, Hungary.
  • 6 Laboratory of Structural Chemistry and Biology, Eötvös Loránd University, Budapest, Hungary; MTA-ELTE Protein Modelling Research Group, Eötvös Loránd University, Budapest, Hungary.
  • 7 Department of Experimental Pharmacology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, Hungary.
  • 8 Medicinal Chemistry Research Group, Research Centre for Natural Sciences, and National Drug Discovery and Development Laboratory, Budapest, Hungary; Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Budapest, Hungary. Electronic address: keseru.gyorgy@ttk.hu.
PMID: 36842271 DOI: 10.1016/j.ejmech.2023.115212
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 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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-W016889
    99.84%, KRasG12C Inhibitor
    Ras
  • HY-W041315
    ≥98.0%, KRasG12C Inhibitor
    Ras