Therapeutic Targeting of Oncogenic K‐Ras by a Covalent Catalytic Site Inhibitor
Sang Min Lim(Harvard University), Kenneth D. Westover(The University of Texas Southwestern Medical Center), Scott B. Ficarro(Dana-Farber Cancer Institute), Rane A. Harrison(Northeastern University), Hwan Geun Choi(Harvard University), Michael E. Pacold(Dana-Farber Cancer Institute), Martin A. Carrasco(The University of Texas Southwestern Medical Center), John C. Hunter(The University of Texas Southwestern Medical Center), Nam Doo Kim(Daegu-Gyeongbuk Medical Innovation Foundation), Ting Xie(Harvard University), Taebo Sim(Korea Institute of Science and Technology), Pasi A. Jänne(Dana-Farber Cancer Institute), Matthew Meyerson(Broad Institute), Jarrod A. Marto(Dana-Farber Cancer Institute), John R. Engen(Northeastern University), Nathanael S. Gray(Harvard University)
Cited by 301Open Access
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.
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