2. Academic Validation
  3. Therapeutic targeting of oncogenic K-Ras by a covalent catalytic site inhibitor

Therapeutic targeting of oncogenic K-Ras by a covalent catalytic site inhibitor

  • Angew Chem Int Ed Engl. 2014 Jan 3;53(1):199-204. doi: 10.1002/anie.201307387.
Sang Min Lim 1,  Kenneth D Westover,  Scott B Ficarro,  Rane A Harrison,  Hwan Geun Choi,  Michael E Pacold,  Martin Carrasco,  John Hunter,  Nam Doo Kim,  Ting Xie,  Taebo Sim,  Pasi A Jänne,  Matthew Meyerson,  Jarrod A Marto,  John R Engen,  Nathanael S Gray
Affiliations

Affiliation

  • 1 Department of Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215 (USA); Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 250 Longwood Avenue, Boston, MA 02115 (USA); Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138 (USA).
PMID: 24259466 DOI: 10.1002/anie.201307387
Abstract

We report the synthesis of a GDP analogue, SML-8-73-1, and a prodrug derivative, SML-10-70-1, which are selective, direct-acting covalent inhibitors of the K-Ras G12C mutant relative to wild-type Ras. Biochemical and biophysical measurements suggest that modification of K-Ras with SML-8-73-1 renders the protein in an inactive state. These first-in-class covalent K-Ras inhibitors demonstrate that irreversible targeting of the K-Ras guanine-nucleotide binding site is potentially a viable therapeutic strategy for inhibition of Ras signaling.

Keywords

K-Ras; cancer; covalent inhibitors; drug design.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-164389
    K-Ras Ligand
    Ras