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

Sang Min Lim, 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

Research output: Contribution to journalArticle

173 Scopus citations

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. Putting a stop to Ras: Two new selective, direct-acting covalent inhibitors of the K-Ras G12C mutant are reported. Studies suggest that the modification of K-Ras with SML-8-73-1 renders the protein inactive. These novel covalent inhibitors demonstrate that irreversible targeting of the K-Ras guanine-nucleotide binding site is potentially a viable therapeutic strategy for inhibition of Ras signaling.

Original languageEnglish (US)
Pages (from-to)199-204
Number of pages6
JournalAngewandte Chemie - International Edition
Volume53
Issue number1
DOIs
Publication statusPublished - Jan 3 2014

    Fingerprint

Keywords

  • cancer
  • covalent inhibitors
  • drug design
  • K-Ras

ASJC Scopus subject areas

  • Chemistry(all)
  • Catalysis

Cite this

Lim, S. M., Westover, K. D., Ficarro, S. B., Harrison, R. A., Choi, H. G., Pacold, M. E., ... Gray, N. S. (2014). Therapeutic targeting of oncogenic K-ras by a covalent catalytic site inhibitor. Angewandte Chemie - International Edition, 53(1), 199-204. https://doi.org/10.1002/anie.201307387