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Updated: Aug 31, 2025
Fully Processed Recombinant KRAS4b: Isolating and Characterizing the Farnesylated and Methylated Protein
Published on: January 16, 2020
Chemoselective Covalent Modification of K-Ras(G12R) with a Small Molecule Electrophile
Ziyang Zhang1,2, Johannes Morstein1, Andrew K Ecker1
1Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California San Francisco, San Francisco, California 94158, United States.
Abstract:
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.
Insights
Researchers discovered new covalent ligands targeting the K-Ras(G12R) mutation, a common cancer driver. This breakthrough enables selective inhibition of this specific KRAS mutant, paving the way for novel cancer therapies.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- KRAS mutations are frequent drivers of human cancers.
- Targeting KRAS mutations with small molecule inhibitors is a key therapeutic strategy.
- Developing allele-specific inhibitors for KRAS mutants beyond G12C remains a significant challenge.
Purpose of the Study:
- To discover covalent chemical ligands targeting the oncogenic K-Ras(G12R) mutant.
- To explore the mechanism of covalent binding to the arginine residue in K-Ras(G12R).
- To establish a foundation for developing mutant-specific therapies for K-Ras(G12R)-driven cancers.
Main Methods:
- Discovery of covalent chemical ligands.
- Biochemical assays to assess ligand binding and reactivity.
- X-ray crystallography to determine the binding mode and chemical adduct.
Main Results:
- Identification of covalent ligands that bind to the Switch II pocket of K-Ras(G12R).
- Demonstration of irreversible reaction with the mutant arginine residue (Arginine 12).
- X-ray crystal structure revealed an imidazolium condensation product formed between the ligand and arginine.
Conclusions:
- Arginine residues can be selectively targeted by small molecule electrophiles.
- The discovered ligands provide a basis for developing therapies against K-Ras(G12R) cancers.
- This work expands the druggability of KRAS mutants beyond the G12C variant.
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