期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 53, 期 1, 页码 199-204出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201307387
关键词
cancer; covalent inhibitors; drug design; K-Ras
资金
- CPRIT [R1207]
- Welch Foundation [I1829]
- NIH [P01NS047572]
- Strategic Research Initiative at the Dana Farber Cancer Institute
- Dana Farber Cancer Institute/Northeastern University Joint Program in Cancer Drug Development [NIH GM101135]
- research collaboration with the Waters Corp
- Sally Gordon Fellowship of the Damon Runyon Cancer Research Foundation [DRG 112-12]
- DOD Breast Cancer Research Program Postdoctoral Fellowship [BC120208]
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.
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