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- Title
Therapeutic Targeting of Oncogenic K-Ras by a Covalent Catalytic Site Inhibitor.
- Authors
Lim, Sang Min; Westover, Kenneth D.; Ficarro, Scott B.; Harrison, Rane A.; Choi, Hwan Geun; Pacold, Michael E.; Carrasco, Martin; Hunter, John; Kim, Nam Doo; Xie, Ting; Sim, Taebo; Jänne, Pasi A.; Meyerson, Matthew; Marto, Jarrod A.; Engen, John R.; Gray, Nathanael S.
- 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.
- Subjects
COVALENT bonds; CHEMICAL synthesis; PRODRUGS; BIOCHEMISTRY; BIOPHYSICS
- Publication
Angewandte Chemie International Edition, 2014, Vol 53, Issue 1, p199
- ISSN
1433-7851
- Publication type
Article
- DOI
10.1002/anie.201307387