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Therapeutic Targeting of Oncogenic K‐Ras by a Covalent Catalytic Site Inhibitor
Author(s) -
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.
Publication year - 2014
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201307387
Subject(s) - covalent bond , prodrug , guanine , chemistry , guanine nucleotide exchange factor , mutant , biochemistry , nucleotide , stereochemistry , signal transduction , gene , organic chemistry
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.