KRAS is vulnerable to reversible switch-II pocket engagement in cells
Open accessPublished version of a preprint
Abstract
Current small-molecule inhibitors of KRAS(G12C) bind irreversibly in the switch-II pocket (SII-P), exploiting the strong nucleophilicity of the acquired cysteine as well as the preponderance of the GDP-bound form of this mutant. Nevertheless, many oncogenic KRAS mutants lack these two features, and it remains unknown whether targeting the SII-P is a practical therapeutic approach for KRAS mutants beyond G12C. Here we use NMR spectroscopy and a cellular KRAS engagement assay to address this question by examining a collection of SII-P ligands from the literature and from our own laboratory. We show that the SII-Ps of many KRAS hotspot (G12, G13, Q61) mutants are accessible using noncovalent ligands, and that this accessibility is not necessarily coupled to the GDP state of KRAS. The results we describe here emphasize the SII-P as a privileged drug-binding site on KRAS and unveil new therapeutic opportunities in RAS-driven cancer.
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Vasta et al. used NMR spectroscopy and BRET-based engagement assays to show that the switch 2 pocket of several non-G12C KRAS mutants can be targeted noncovalently without requiring the protein to be GDP-bound.
“Vasta et al.177 have used NMR spectroscopy and competitive bioluminescence resonance energy transfer (BRET)-based engagement assays to demonstrate that the switch 2 pocket of several other non-G12C mutants of KRAS can be targeted in a noncovalent manner that is not reliant on the protein being GDP bound.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [177]
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References 43 · Cited by 115
- Authors
- Vasta, J. D., Peacock, D. M., Zheng, Q., Walker, J. A., Zhang, Z., Zimprich, C. A., Thomas, M. R., Beck, M. T., Binkowski, B. F., Corona, C. R., Robers, M. B., & Shokat, K. M.
- Affiliations
- Promega (United States) (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Robers, Matthew B.
- Shokat, Kevan M.
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2022-03-21
- Volume
- 18
- Issue
- 6
- Pages
- 596-604
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC9135634
- OpenAlex
- W4221126430
- Cited by
- 115
- References
- 43
- Citations by year
- 2026: 21 · 2025: 22 · 2024: 25 · 2023: 26 · 2022: 21
- FWCI
- 7.80
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature Chemical Biology (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- Promega Corporation
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (F32CA253966)
- Damon Runyon Cancer Research Foundation (DRG-2434-21, DRG-2281-17)
- Howard Hughes Medical Institute
- 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, switch-II pocket, KRAS G12C, GDP-bound state, RAS-driven cancers, small molecule inhibitors
- MeSH terms
- Humans, Ligands, Multiple Myeloma, Mutation, Proto-Oncogene Proteins p21(ras)
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