| Affiliation: | 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);4. Departments of Biochemistry and Radiation Oncology, The University of Texas, Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390 (USA);5. Blais Proteomics Center, Dana‐Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02115 (USA);6. Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Avenue, Boston, MA 02115 (USA);7. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02139 (USA);8. New Drug Development Center, Daegu‐Gyeongbuk Medical Innovation Foundation, Daegu, 706‐010 (South Korea);9. Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, 130‐650 (South Korea);10. Department of Medical Oncology, Dana‐Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02115 (USA);11. Broad Institute of Harvard and MIT, 320 Charles St., Cambridge, MA 02141 (USA);12. Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115 (USA) |
| 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. |
