Chemoselective Covalent Modification of K-Ras(G12R) with a Small Molecule Electrophile
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High Resolution Image Download MS PowerPoint Slide KRAS mutations are one of the most common oncogenic drivers in human cancer. While small molecule inhibitors for the G12C mutant have been successfully developed, allele-specific inhibition for other KRAS hotspot mutants remains challenging. Here we report the discovery of covalent chemical ligands for the common oncogenic mutant K-Ras(G12R). These ligands bind in the Switch II pocket and irreversibly react with the mutant arginine residue. An X-ray crystal structure reveals an imidazolium condensation product formed between the α,β-diketoamide ligand and the ε- and η-nitrogens of arginine 12. Our results show that arginine residues can be selectively targeted with small molecule electrophiles despite their weak nucleophilicity and provide the basis for the development of mutant-specific therapies for K-Ras(G12R)-driven cancer.
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The Shokat lab identified electrophiles with the potential for developing G12R-selective inhibitors.
“Furthermore, the Shokat lab identified electrophiles with the potential for developing G12R-selective inhibitors [60].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [60]
In 2022, Shokat and colleagues reported the development of covalent inhibitors of KRASG12S mutants and KRASG12R mutants.
“In 2022, Shokat and colleagues reported the development of covalent inhibitors of KRASG12S mutants and KRASG12R mutants.93,94”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [94]
X-ray crystal structure revealed that G12R inhibitor-4 irreversibly reacts with mutant arginine residues in S-IIP, showing imidazole condensation products formed between the α,β-diketoamide ligand and ε-,η-nitrogen of Arg12.
“The irreversible reaction of G12R inhibitor-4 combined with mutant arginine residues in S-II P was revealed by X-ray crystal structure, which showed imidazole condensation products formed between the α, β-diketoamide ligand and ε-, η- nitrogen of Arg12.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [94]
Although arginine residues are less nucleophilic, they can be selectively targeted by small, electrophilic molecular reagents, providing the basis for development of mutant-specific therapies against KRASG12R-driven cancers.
“Although arginine residues are less nucleophilic, they can be selectively targeted by small, electronphilic molecular reagents, providing the basis for the development of mutant-specific therapies against KRASG12R-driven cancers.94”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [94]
Shokat and colleagues developed KRASG12R covalent inhibitors, G12R inhibitor-4, by introducing α,β-diketoamide structures that covalently target arginine.
“Similarly, they successfully developed KRASG12R covalent inhibitors, G12R inhibitor-4 (25), by introducing α, β-diketoamide structures that covalently target arginine.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [94]
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- Authors
- Zhang, Z., Morstein, J., Ecker, A. K., Guiley, K. Z., & Shokat, K. M.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Zhang, Ziyang
- Shokat, Kevan M.
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2022-08-24
- Volume
- 144
- Issue
- 35
- Pages
- 15916-15921
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- PMC
- PMC9460778
- OpenAlex
- W4293010883
- Cited by
- 159
- References
- 39
- Citations by year
- 2026: 25 · 2025: 50 · 2024: 45 · 2023: 33 · 2022: 6
- FWCI
- 11.01
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Journal of the American Chemical Society (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (1R01CA244550, K00CA253758)
- Damon Runyon Cancer Research Foundation (DRG-2281-17, DRG-2399-20)
- Samuel Waxman Cancer Research Foundation
- National Institute of General Medical Sciences (5T32GM64337-20)
- Mark Foundation For Cancer Research
- 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 › Chemistry › Organic Chemistry › Synthesis and biological activity
- Keywords
- covalent inhibitors, switch-II pocket, chemoselective modification, KRAS mutation, oncogenic KRAS, crystal structure
- MeSH terms
- Arginine, Humans, Ligands, Mutation, Neoplasms, Genes, ras, Proto-Oncogene Proteins p21(ras)
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