Discovery of N‑(1-Acryloylazetidin-3-yl)-2-(1H‑indol-1-yl)acetamides as Covalent Inhibitors of
KRASG12C

Shin, Youngsook; Jeong, Joon Won; Wurz, Ryan P.; Achanta, Pragathi; Arvedson, Tara; Bartberger, Michael D.; Campuzano, Iain D. G.; Fucini, Ray; Hansen, Stig K.; Ingersoll, John; Iwig, Jeffrey S.; Lipford, J. Russell; Ma, Vu; Kopecky, David J.; McCarter, John; San Miguel, Tisha; Mohr, Christopher; Sabet, Sudi; Saiki, Anne Y.; Sawayama, Andrew; Sethofer, Steven; Tegley, Christopher M.; Volak, Laurie P.; Yang, Kevin; Lanman, Brian A.; Erlanson, Daniel A.; Cee, Victor J.

doi:10.1021/acsmedchemlett.9b00258.s001

ml9b00258_si_001.pdf (622.88 kB)

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

journal contribution

posted on 2019-08-20, 18:58 authored by Youngsook Shin, Joon Won Jeong, Ryan P. Wurz, Pragathi Achanta, Tara Arvedson, Michael D. Bartberger, Iain D. G. Campuzano, Ray Fucini, Stig K. Hansen, John Ingersoll, Jeffrey S. Iwig, J. Russell Lipford, Vu Ma, David J. Kopecky, John McCarter, Tisha San Miguel, Christopher Mohr, Sudi Sabet, Anne Y. Saiki, Andrew Sawayama, Steven Sethofer, Christopher M. Tegley, Laurie P. Volak, Kevin Yang, Brian A. Lanman, Daniel A. Erlanson, Victor J. Cee

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.