Discovery of <i>N</i>-(1-Acryloylazetidin-3-yl)-2-(1<i>H</i>-indol-1-yl)acetamides as Covalent Inhibitors of KRAS<sup>G12C</sup>.
Shin Y, Jeong JW, Wurz RP, Achanta P, Arvedson T, Bartberger MD, Campuzano IDG, Fucini R, Hansen SK, Ingersoll J, Iwig JS, Lipford JR, Ma V, Kopecky DJ, McCarter J, San Miguel T, Mohr C, Sabet S, Saiki AY, Sawayama A, Sethofer S, Tegley CM, Volak LP, Yang K, Lanman BA, Erlanson DA, Cee VJ.
KRAS regulates many cellular processes including proliferation, survival, and differentiation. Point mutants of KRAS have long been known to be molecular drivers of cancer. <i>KRAS p.G12C</i>, 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<sup>G12C</sup> 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<sup>G12C</sup> with submicromolar inhibition of downstream signaling in a KRAS<sup>G12C</sup>-specific manner.