The DOI matches its Crossref record; 38 of the 39 references it cites were found in a registry or an index.
The reactivity-driven biochemical mechanism of covalent KRASG12C inhibitors
Abstract
Activating mutations in KRAS are among the most common tumor driver mutations. Until recently, KRAS had been considered undruggable with small molecules; the discovery of the covalent KRAS G12C inhibitors ARS-853 and ARS-1620 has demonstrated that it is feasible to inhibit KRAS with high potency in cells and animals. Although the biological activity of these inhibitors has been described, the biochemical mechanism of how the compounds achieve potent inhibition remained incompletely understood. We now show that the activity of ARS-853 and ARS-1620 is primarily driven by KRAS-mediated catalysis of the chemical reaction with Cys12 in human KRAS G12C, while the reversible binding affinity is weak, in the hundreds of micromolar or higher range. The mechanism resolves how an induced, shallow and dynamic pocket not expected to support high-affinity binding of small molecules can nevertheless be targeted with potent inhibitors and may be applicable to other targets conventionally considered undruggable.
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“G12C-Is bind an evanescent pocket in KRAS-GDP, positioning a reactive group to couple to the mutant cysteine.”
From SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling (2021) · cites this paper as Hansen et al., 2018
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Metadata
- Authors
- Hansen, R., Peters, U., Babbar, A., Chen, Y., Feng, J., Janes, M. R., Li, L.-S., Ren, P., Liu, Y., & Zarrinkar, P. P.
- Affiliations
- Wellspring Biosciences (United States) (US)
- Kura Oncology (United States) (US)
- Corresponding author
- Zarrinkar, Patrick P.
- Venue
- Nature Structural & Molecular Biology
- Published
- 2018-05-14
- Volume
- 25
- Issue
- 6
- Pages
- 454-462
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- OpenAlex
- W2800484366
- Cited by
- 153
- References
- 39
- Citations by year
- 2026: 14 · 2025: 18 · 2024: 20 · 2023: 16 · 2022: 20 · 2021: 15 · 2020: 25 · 2019: 19 · 2018: 5
- FWCI
- 6.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- KRAS G12C, covalent inhibitors, undruggable targets, enzyme kinetics, small molecule inhibitors
- MeSH terms
- Animals, Catalysis, Cysteine, Humans, Kinetics, Mutation, Neoplasms, Protein Binding, Genes, ras, ras Proteins
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