Discovery of <i>N</i>-(1-Acryloylazetidin-3-yl)-2-(1<i>H</i>-indol-1-yl)acetamides as Covalent Inhibitors of KRAS^G12C

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. <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^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.