Cited by 119Protein Kinase Regulation and GTPase SignalingHeterocyclic Compound Synthesis and BioactivityLung Cancer Treatments and Mutations

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

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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.·2019·ACS Medicinal Chemistry Letters

DOI 10.1021/acsmedchemlett.9b00258PMC PMC6746093

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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. 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.

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A chemoproteomic platform for reactive fragment profiling against the deubiquitinasesPreprint
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KRAS Inhibitors
Corey, E. J., & Wu, Y. (2023) · Wiley eBooks · doi:10.1002/9781394207145.ch21

Authors: Shin, Y., Jeong, J. W., Wurz, R. P., Achanta, P., Arvedson, T., Bartberger, M. D., Campuzano, I. D. G., Fucini, R., Hansen, S. K., Ingersoll, J., Iwig, J. S., Lipford, J. R., Ma, V., Kopecky, D. J., McCarter, J., San Miguel, T., Mohr, C., Sabet, S., Saiki, A. Y., Sawayama, A., Sethofer, S., Tegley, C. M., Volak, L. P., Yang, K., Lanman, B. A., Erlanson, D. A., & Cee, V. J.
Affiliations: Amgen (United States) (US)
Carmot Therapeutics (United States) (US)
Carmot Therapeutics, Inc. 740 Heinz Avenue, Berkeley, California 94710, United States
Corresponding author: Erlanson, Daniel A.
Cee, Victor J.
ORCID: Shin, Youngsook
Jeong, Joon Won
Wurz, Ryan P.
Arvedson, Tara
Bartberger, Michael D.
Campuzano, Iain D. G.
Hansen, Stig K.
Saiki, Anne Y.
Volak, Laurie P.
Yang, Kevin
Lanman, Brian A.
Erlanson, Daniel A.
Cee, Victor J.
Venue: ACS Medicinal Chemistry Letters
Publisher: American Chemical Society (ACS)
Published: 2019-08-20
Volume: 10
Issue: 9
Pages: 1302-1308
ISSN: 1948-5875 (ISSN-L)
DOI: 10.1021/acsmedchemlett.9b00258
PMC: PMC6746093
OpenAlex: W2969336671
Cited by: 113
References: 18
Citations by year: 2026: 16 · 2025: 17 · 2024: 15 · 2023: 21 · 2022: 22 · 2021: 8 · 2020: 12 · 2019: 2
FWCI: 3.89
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-045 (stm-asf)
Locations: ACS Medicinal Chemistry Letters (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (1s10od021832-01)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Physical Sciences › Chemistry › Organic Chemistry › Heterocyclic Compound Synthesis and Bioactivity
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Keywords: KRAS G12C, covalent inhibitors, lung adenocarcinoma, colorectal cancer, surface grooves, structure-based design

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

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