Get access

Therapeutic Targeting of Oncogenic K-Ras by a Covalent Catalytic Site Inhibitor

Authors

  • Dr. Sang Min Lim,

    1. Department of Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215 (USA)
    2. Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 250 Longwood Avenue, Boston, MA 02115 (USA)
    3. Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138 (USA)
    Search for more papers by this author
    • These authors contributed equally to this work.

  • Dr. Kenneth D. Westover,

    1. Departments of Biochemistry and Radiation Oncology, The University of Texas, Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390 (USA)
    Search for more papers by this author
    • These authors contributed equally to this work.

  • Dr. Scott B. Ficarro,

    1. Department of Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215 (USA)
    2. Blais Proteomics Center, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02115 (USA)
    Search for more papers by this author
  • Rane A. Harrison,

    1. Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Avenue, Boston, MA 02115 (USA)
    Search for more papers by this author
  • Dr. Hwan Geun Choi,

    1. Department of Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215 (USA)
    2. Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 250 Longwood Avenue, Boston, MA 02115 (USA)
    Search for more papers by this author
  • Dr. Michael E. Pacold,

    1. Department of Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215 (USA)
    2. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02139 (USA)
    Search for more papers by this author
  • Dr. Martin Carrasco,

    1. Departments of Biochemistry and Radiation Oncology, The University of Texas, Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390 (USA)
    Search for more papers by this author
  • Dr. John Hunter,

    1. Departments of Biochemistry and Radiation Oncology, The University of Texas, Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390 (USA)
    Search for more papers by this author
  • Dr. Nam Doo Kim,

    1. New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 706-010 (South Korea)
    Search for more papers by this author
  • Ting Xie,

    1. Department of Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215 (USA)
    2. Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 250 Longwood Avenue, Boston, MA 02115 (USA)
    3. Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138 (USA)
    Search for more papers by this author
  • Dr. Taebo Sim,

    1. Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, 130-650 (South Korea)
    Search for more papers by this author
  • Dr. Pasi A. Jänne,

    1. Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02115 (USA)
    Search for more papers by this author
  • Dr. Matthew Meyerson,

    1. Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02115 (USA)
    2. Broad Institute of Harvard and MIT, 320 Charles St., Cambridge, MA 02141 (USA)
    3. Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115 (USA)
    Search for more papers by this author
  • Dr. Jarrod A. Marto,

    1. Department of Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215 (USA)
    2. Blais Proteomics Center, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02115 (USA)
    Search for more papers by this author
  • Dr. John R. Engen,

    1. Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Avenue, Boston, MA 02115 (USA)
    Search for more papers by this author
  • Dr. Nathanael S. Gray

    Corresponding author
    1. Department of Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215 (USA)
    2. Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 250 Longwood Avenue, Boston, MA 02115 (USA)
    • Department of Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215 (USA)

    Search for more papers by this author

  • This work was supported by CPRIT (R1207), The Welch Foundation (I1829), NIH P01NS047572, the Strategic Research Initiative at the Dana Farber Cancer Institute (J.A.M.), the Dana Farber Cancer Institute/Northeastern University Joint Program in Cancer Drug Development, NIH GM101135 (J.R.E.), a research collaboration with the Waters Corp (J.R.E.), Sally Gordon Fellowship of the Damon Runyon Cancer Research Foundation (DRG 112-12) (M.E.P.), DOD Breast Cancer Research Program Postdoctoral Fellowship (BC120208) (M.E.P.).

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.

Ancillary