Fragment Optimization of Reversible Binding to the Switch II Pocket on KRAS Leads to a Potent, In Vivo Active KRAS G12C Inhibitor
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High Resolution Image Download MS PowerPoint Slide Activating mutations in KRAS are the most frequent oncogenic alterations in cancer. The oncogenic hotspot position 12, located at the lip of the switch II pocket, offers a covalent attachment point for KRAS G12C inhibitors. To date, KRAS G12C inhibitors have been discovered by first covalently binding to the cysteine at position 12 and then optimizing pocket binding. We report on the discovery of the in vivo active KRAS G12C inhibitor BI-0474 using a different approach, in which small molecules that bind reversibly to the switch II pocket were identified and then optimized for non-covalent binding using structure-based design. Finally, the Michael acceptor containing warhead was attached. Our approach offers not only an alternative approach to discovering KRAS G12C inhibitors but also provides a starting point for the discovery of inhibitors against other oncogenic KRAS mutants.
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BI-1823911 is a novel, powerful and highly selective covalent irreversible KRASG12C oral small molecule inhibitor.
“It is a novel, powerful and highly selective covalent irreversible KRASG12C oral small molecule inhibitor, intended for the treatment of patients with unresectable, locally advanced, or metastatic solid tumors carrying KRASG12C specific oncogene mutation.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [75]
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- Authors
- Bröker, J., Waterson, A. G., Smethurst, C., Kessler, D., Böttcher, J., Mayer, M., Gmaschitz, G., Phan, J., Little, A., Abbott, J. R., Sun, Q., Gmachl, M., Rudolph, D., Arnhof, H., Rumpel, K., Savarese, F., Gerstberger, T., Mischerikow, N., Treu, M., Herdeis, L., Wunberg, T., Gollner, A., Weinstabl, H., Mantoulidis, A., Krämer, O., McConnell, D. B., & W. Fesik, S.
- Affiliations
- Boehringer Ingelheim RCV GmbH & Co. KG, Dr. Boehringer Gasse 5-11, A-1121 Vienna, Austria
- Vanderbilt University (US)
- Boehringer Ingelheim (Austria) (AT)
- Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States
- Corresponding author
- Waterson, Alex G.
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2022-10-27
- Volume
- 65
- Issue
- 21
- Pages
- 14614-14629
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- PMC
- PMC9661478
- OpenAlex
- W4307425458
- Cited by
- 96
- References
- 31
- Citations by year
- 2026: 26 · 2025: 27 · 2024: 28 · 2023: 15
- FWCI
- 5.69
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Medicinal Chemistry (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DORA PSI (Paul Scherrer Institute) (submittedVersion, cc-by-nc-nd)
- Funders
- National Cancer Institute (P50A95103-12)
- ?sterreichische Forschungsf?rderungsgesellschaft (854341, 861507, 867897, 874517, 883626, 892584)
- Lustgarten Foundation
- National Institutes of Health (5DP1OD006933, 5RC2CA148375)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- KRAS G12C inhibitors, switch-II pocket, reversible binding, structure-based drug design, covalent inhibitors, oncogenic KRAS mutations, in vivo potency
- MeSH terms
- Cysteine, Humans, Mutation, Neoplasms, Genes, ras, Proto-Oncogene Proteins p21(ras)
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