| Literature DB >> 31531201 |
Youngsook Shin1, Joon Won Jeong2, Ryan P Wurz1, Pragathi Achanta1, Tara Arvedson1, Michael D Bartberger1, Iain D G Campuzano1, Ray Fucini2, Stig K Hansen2, John Ingersoll1, Jeffrey S Iwig2, J Russell Lipford1, Vu Ma1, David J Kopecky1, John McCarter1, Tisha San Miguel1, Christopher Mohr1, Sudi Sabet2, Anne Y Saiki1, Andrew Sawayama2, Steven Sethofer2, Christopher M Tegley1, Laurie P Volak1, Kevin Yang1, Brian A Lanman1, Daniel A Erlanson2, Victor J Cee1.
Abstract
KRAS regulates many cellular processes including proliferation, survival, and differentiation. Point mutants of KRAS have long been known to be molecular drivers of cancer. KRAS p.G12C, which occurs in approximately 14% of lung adenocarcinomas, 3-5% of colorectal cancers, and low levels in other solid tumors, represents an attractive therapeutic target for covalent inhibitors. Herein, we disclose the discovery of a class of novel, potent, and selective covalent inhibitors of KRASG12C identified through a custom library synthesis and screening platform called Chemotype Evolution and structure-based design. Identification of a hidden surface groove bordered by H95/Y96/Q99 side chains was key to the optimization of this class of molecules. Best-in-series exemplars exhibit a rapid covalent reaction with cysteine 12 of GDP-KRASG12C with submicromolar inhibition of downstream signaling in a KRASG12C-specific manner.Entities:
Year: 2019 PMID： 31531201 PMCID： PMC6746093 DOI： 10.1021/acsmedchemlett.9b00258
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345