Therapeutic Targeting of Oncogenic K-Ras by a Covalent Catalytic Site Inhibitor

Title
Therapeutic Targeting of Oncogenic K-Ras by a Covalent Catalytic Site Inhibitor
Authors
Sang Min LimKenneth D. WestoverScott B. FicarroRane A. HarrisonHwan Geun ChoiMichael E. PacoldMartin CarrascoJohn HunterNam Doo KimTing Xie심태보Pasi A. JanneMatthew MeyersonJarrod A. MartoJohn R. EngenNathanael S. Gray
Keywords
K-Ras; cancer; covalent inhibitors; drug design
Issue Date
2014-01
Publisher
Angewandte Chemie international edition
Citation
VOL 53, NO 1, 199-204
Abstract
We report the synthesis of a GDPanalogue, 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.
URI
http://pubs.kist.re.kr/handle/201004/47053
ISSN
14337851
Appears in Collections:
KIST Publication > Article
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