Discovery of N‑(1-Acryloylazetidin-3-yl)-2-(1H‑indol-1-yl)acetamides as Covalent Inhibitors of
KRASG12C
Posted on 2019-08-20 - 18:58
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.
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Shin, Youngsook; Jeong, Joon Won; Wurz, Ryan P.; Achanta, Pragathi; Arvedson, Tara; Bartberger, Michael D.; et al. (2019). Discovery of N‑(1-Acryloylazetidin-3-yl)-2-(1H‑indol-1-yl)acetamides as Covalent Inhibitors of
KRASG12C. ACS Publications. Collection. https://doi.org/10.1021/acsmedchemlett.9b00258
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AUTHORS (27)
YS
Youngsook Shin
JJ
Joon Won Jeong
RW
Ryan P. Wurz
PA
Pragathi Achanta
TA
Tara Arvedson
MB
Michael D. Bartberger
IC
Iain D. G. Campuzano
RF
Ray Fucini
SH
Stig K. Hansen
JI
John Ingersoll
JI
Jeffrey S. Iwig
JL
J. Russell Lipford
VM
Vu Ma
DK
David J. Kopecky
JM
John McCarter
TS
Tisha San Miguel
CM
Christopher Mohr
SS
Sudi Sabet
AS
Anne Y. Saiki
AS
Andrew Sawayama