In situ selectivity profiling and crystal structure of SML-8-73-1, an active site inhibitor of oncogenic K-Ras G12C
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Significance: SML-8-73-1 (SML) is the first example, to our knowledge, of a GTP-competitive inhibitor of V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (K-Ras). A high-resolution structure of K-Ras G12C bound to SML shows K-Ras in an inactive conformation. In situ proteomic-based chemical profiling of SML demonstrates that SML is highly selective for K-Ras G12C over other small GTPases. A novel chemosensor-based assay allows measurement of covalent reaction rates between K-Ras G12C and SML and enables characterization of this reaction in the context of millimolar concentrations of GTP and GDP, well in exccss of what is found in living cells. These results demonstrate that even in the presence of high concentrations of GTP and GDP, SML is able to exchange into the GN site.
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In simulated cell conditions, after incubation for 2 h, the substrate competitive binding of SML-8-73-1 was more than 95% KRASG12C.
“The results showed that after incubation for 2 h, the substrate competitive binding of SML-8-73-1 was more than 95% KRASG12C.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [90]
Gray et al. developed covalent kinase inhibitors based on GDP/GTP binding sites, providing a new idea for the study of KRASG12C inhibitors, and obtained a series of nucleotide covalent KRASG12C inhibitors.
“Gray et al. developed covalent kinase inhibitors based on GDP/GTP binding sites, providing a new idea for the study of KRASG12C inhibitors, and obtained a series of nucleotide covalent KRASG12C inhibitors.90”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [90]
SML-8-73-1 contains two negatively charged phosphate groups, making it difficult to cross the cell membrane.
“However, SML-8-73-1 contains two negatively charged phosphate groups, making it difficult to cross the cell membrane.86,90”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [90]
Gray et al. designed substrate competition-related covalent inhibitors targeting catalytic sites based on their GDP-based structure, and SML-8-73-1 was identified as the main candidate.
“They first designed a series of substrate competition-related covalent inhibitors targeting catalytic sites based on their GDP-based structure, and SML-8-73-1 (21) was identified as the main candidate.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [90]
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- Authors
- Hunter, J. C., Gurbani, D., Ficarro, S. B., Carrasco, M. A., Lim, S. M., Choi, H. G., Xie, T., Marto, J. A., Chen, Z., Gray, N. S., & Westover, K. D.
- Affiliations
- Departments of Biochemistry and Radiation Oncology and
- Dana-Farber Cancer Institute (US)
- Harvard University (US)
- The University of Texas Southwestern Medical Center (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-06-02
- Volume
- 111
- Issue
- 24
- Pages
- 8895-8900
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4066474
- OpenAlex
- W2165097702
- Cited by
- 242
- References
- 54
- Citations by year
- 2026: 14 · 2025: 23 · 2024: 18 · 2023: 18 · 2022: 16 · 2021: 20 · 2020: 31 · 2019: 21 · 2018: 19 · 2017: 21 · 2016: 22 · 2015: 15 · 2014: 3
- FWCI
- 8.33
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Energy
- Welch Foundation
- Cancer Prevention and Research Institute of Texas (R1207)
- University of Chicago
- Biological and Environmental Research
- Argonne National Laboratory
- 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 › Receptor Mechanisms and Signaling
- Keywords
- oncogenic Ras, irreversible covalent inhibitors, switch I region, selectivity profiling, X-ray crystal structure
- MeSH terms
- Acetamides, Binding Sites, Biotin, Guanosine Diphosphate, Guanosine Triphosphate, Humans, Ligands, Models, Molecular, Mutation, Protein Binding, Protein Conformation, Genes, ras, Signal Transduction, Conserved Sequence, Crystallography, X-Ray, ras Proteins, GTP-Binding Proteins, Phosphatidylinositol 3-Kinases, Catalytic Domain, GTP Phosphohydrolases, Proteomics
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 ›
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