The DOI matches its Crossref record; 17 of the 18 references it cites were found in a registry or an index.
Discovery of N-(1-Acryloylazetidin-3-yl)-2-(1 H-indol-1-yl)acetamides as Covalent Inhibitors of KRASG12C
Open accessAbstract
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“A library of 3,300 acrylamides was screened in three assays: a thiol reactivity assay, a RAF-coupled nucleotide exchange assay and an intact MS assay158.”
From Advances in covalent drug discovery (2022) · cites this paper as [158]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Targeting RAS signalling pathways in cancer therapy
Downward, J. (2003) · Nature reviews. Cancer · doi:10.1038/nrc969 · Cited by 3,354
K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions
Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A., & Shokat, K. M. (2013) · Nature · doi:10.1038/nature12796 · Cited by 2,557
Drugging the undruggable RAS: Mission Possible?
Cox, A. D., Fesik, S. W., Kimmelman, A. C., Luo, J., & Der, C. J. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4389 · Cited by 1,997
AACR Project GENIE: Powering Precision Medicine through an International Consortium
The AACR Project GENIE Consortium, The AACR Project GENIE Consortium, André, F., Arnedos, M., Baras, A. S., Baselga, J., Bedard, P. L., Berger, M. F., Bierkens, M., Calvo, F., et al. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-17-0151 · Cited by 1,964
The Ras superfamily at a glance
Wennerberg, K., Rossman, K. L., & Der, C. J. (2005) · Journal of Cell Science · doi:10.1242/jcs.01660 · Cited by 1,549
Ras oncogenes: split personalities
Karnoub, A. E., & Weinberg, R. A. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2438 · Cited by 1,467
Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor
Janes, M. R., Zhang, J., Li, L.-S., Hansen, R., Peters, U., Guo, X., Chen, Y., Babbar, A., Firdaus, S. J., Darjania, L., et al. (2018) · Cell · doi:10.1016/j.cell.2018.01.006 · Cited by 1,172
Blocking Oncogenic Ras Signaling for Cancer Therapy
Adjei, A. A. (2001) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/93.14.1062 · Cited by 836
Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state
Patricelli, M. P., Janes, M. R., Li, L.-S., Hansen, R., Peters, U., Kessler, L. V., Chen, Y., Kucharski, J. M., Feng, J., Ely, T., et al. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-1105 · Cited by 759
Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design
Ostrem, J. M. L., & Shokat, K. M. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.139 · Cited by 641
Site-directed ligand discovery
Erlanson, D. A., Braisted, A. C., Raphael, D. R., Randal, M., Stroud, R. M., Gordon, E. M., & Wells, J. A. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.17.9367 · Cited by 466
Self-citationFlanagan, M. E., Abramite, J. A., Anderson, D. P., AULABAUGH, A. E., Dahal, U. P., Gilbert, A. M., Li, C., Montgomery, J. I., Oppenheimer, S. R., Ryder, T. F., et al. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm501412a · Cited by 337
Novel Allosteric Sites on Ras for Lead Generation
Grant, B. J., Lukman, S., Hocker, H. J., Sayyah, J., Brown, J. H., McCammon, J. A., & Gorfe, A. A. (2011) · PLoS ONE · doi:10.1371/journal.pone.0025711 · Cited by 180
Cee, V. J., Volak, L. P., Chen, Y., Bartberger, M. D., Tegley, C. M., Arvedson, T., McCarter, J. D., Tasker, A. S., & Fotsch, C. H. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b01018 · Cited by 165
Self-citationCampuzano, I. D. G., Miguel, T. S., Rowe, T., Onea, D., Cee, V. J., Arvedson, T., & McCarter, J. D. (2015) · SLAS DISCOVERY · doi:10.1177/1087057115621288 · Cited by 64
Self-citationSynthesis of Diverse N-Acryloyl Azetidines and Evaluation of Their Enhanced Thiol Reactivities
Palkowitz, M. D., Tan, B., Hu, H., Roth, K. D. W., & Bauer, R. A. (2017) · Organic Letters · doi:10.1021/acs.orglett.7b00788 · Cited by 23
Lanman, B. A., Chen, J. J., Liu, L., Lopez, P., Pickrell, A. J., Reed, A. B., Wang, H., Achanta, P., Canon, J. R., Erlanson, D. A., et al. (2019) · Cancer Research · doi:10.1158/1538-7445.am2019-4455 · Cited by 9
Self-citation
Cited by
Sorted by citations
Advances in covalent drug discovery
Boike, L., Henning, N. J., & Nomura, D. K. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00542-z · Cited by 823
Discovery of a Covalent Inhibitor of KRAS G12C (AMG 510) for the Treatment of Solid Tumors
Lanman, B. A., Allen, J. R., Allen, J. G., Amegadzie, A. K., Ashton, K. S., Booker, S. K., Chen, J. J., Chen, N., Frohn, M. J., Goodman, G., et al. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01180 · Cited by 765
Self-citationRecent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
Xie, X., Yu, T., Li, X., Zhang, N., Foster, L. J., Peng, C., Huang, W., & He, G. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01589-z · Cited by 396
Crystal structure of human KRAS G12C covalently bound to a phthalazine inhibitor
Mohr, C. (2019) · Worldwide Protein Data Bank · doi:10.2210/pdb6pgo/pdb · Cited by 313
Self-citationThe current understanding of KRAS protein structure and dynamics
Pantsar, T. (2019) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2019.12.004 · Cited by 304
Metadata
- 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
- 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)
- 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
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
