Open AccessDiscovery of N-(1-Acryloylazetidin-3-yl)-2-(1H-indol-1-yl)acetamides as Covalent Inhibitors of KRASG12C
Author(s) -
Youngsook Shin,
Joon Won Jeong,
Ryan P. Wurz,
Pragathi Achanta,
Tara Arvedson,
Michael D. Bartberger,
Iain D. G. Campuzano,
Ray Fucini,
Steven G. Hansen,
J. G. Ingersoll,
Jeffrey S. Iwig,
J. Russell Lipford,
Vu Ma,
David J. Kopecky,
John D. McCarter,
Tisha San Miguel,
Christopher Mohr,
Sudi Sabet,
Anne Y. Saiki,
Andrew M. Sawayama,
Steven G. Sethofer,
Christopher M. Tegley,
Laurie P. Volak,
Kevin Yang,
Brian A. Lanman,
Daniel A. Erlanson,
Victor J. Cee
Publication year - 2019
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00258
Subject(s) - covalent bond , kras , combinatorial chemistry , chemistry , biochemistry , organic chemistry , mutation , gene
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 KRAS G12C 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-KRAS G12C with submicromolar inhibition of downstream signaling in a KRAS G12C -specific manner.