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Angew Chem Int Ed Engl. 2014 Jan 3;53(1):199-204. doi: 10.1002/anie.201307387. Epub 2013 Nov 20.

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

Author information

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).

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

PMID:
24259466
PMCID:
PMC3914205
DOI:
10.1002/anie.201307387
[Indexed for MEDLINE]
Free PMC Article
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