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. Epub 2013 Nov 20.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catalytic Domain / genetics*
  • Drug Design
  • Signal Transduction
  • ras Proteins / chemistry*
  • ras Proteins / genetics*
  • ras Proteins / metabolism


  • ras Proteins