ArticleProceedings of the National Academy of Sciences of the United States of America2020
Small-molecule covalent bond formation at tyrosine creates a binding site and inhibits activation of Ral GTPases.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 46 citations in OpenAlex.
- Protein structural dynamics in covalent drug design: insights from irreversible and reversible covalent inhibitors.RSC chemical biology · 2026Review
- A Fragment-Based Electrophile-First Approach to Target Histidine with Aryl-Fluorosulfates: Application to hMcl-1.Journal of medicinal chemistry · 2025Article
- Small-Molecule KRAS Inhibitors by Tyrosine Covalent Bond Formation.ChemMedChem · 2025Article
- Advances in sulfonyl exchange chemical biology: expanding druggable target space.Chemical science · 2025Review
- Proximity-induced SuFEx increases the potency of cytosolic nucleotidase inhibitors and reveals a rare example of covalently targeted histidine.RSC chemical biology · 2025Article
- Pioneer in Molecular Biology: Conformational Ensembles in Molecular Recognition, Allostery, and Cell Function.Journal of molecular biology · 2025Review
- Advances in reversible covalent kinase inhibitors.Medicinal research reviews · 2025Review
- mTOR Variants Activation Discovers PI3K-like Cryptic Pocket, Expanding Allosteric, Mutant-Selective Inhibitor Designs.Journal of chemical information and modeling · 2025Article
- Covalent Targeting of Histidine Residues with Aryl Fluorosulfates: Application to Mcl-1 BH3 Mimetics.Journal of medicinal chemistry · 2024Article
- Regulation of Ras p21 and RalA GTPases activity by quinine in mammary epithelial cells.Molecular and cellular biochemistry · 2024Article
- NU6300 covalently reacts with cysteine-191 of gasdermin D to block its cleavage and palmitoylation.Science advances · 2024Article
- Direct mapping of ligandable tyrosines and lysines in cells with chiral sulfonyl fluoride probes.Nature chemistry · 2023Article
- Exploring Covalent Bond Formation at Tyr-82 for Inhibition of Ral GTPase Activation.ChemMedChem · 2023Article
- Sulfur fluoride exchange.Nature reviews. Methods primers · 2023Article
- Higher-order interactions of Bcr-Abl can broaden chronic myeloid leukemia (CML) drug repertoire.Protein science : a publication of the Protein Society · 2023Article
- Allostery: Allosteric Cancer Drivers and Innovative Allosteric Drugs.Journal of molecular biology · 2022Review
- Deciphering Conformational Changes of the GDP-Bound NRAS Induced by Mutations G13D, Q61R, and C118S through Gaussian Accelerated Molecular Dynamic Simulations.Molecules (Basel, Switzerland) · 2022Article
- Mechanism of activation and the rewired network: New drug design concepts.Medicinal research reviews · 2022Review
- Q61 mutant-mediated dynamics changes of the GTP-KRAS complex probed by Gaussian accelerated molecular dynamics and free energy landscapes.RSC advances · 2022Article
- Synthesis, Antibacterial and Insecticidal Activities of Novel Capsaicin Derivatives Containing a Sulfonic Acid Esters Moiety.Frontiers in chemistry · 2022Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Ral (Ras-like) GTPases are directly activated by oncogenic Ras GTPases. Mutant K-Ras (G12C) has enabled the development of covalent K-Ras inhibitors currently in clinical trials. However, Ral, and the overwhelming majority of mutant oncogenic K-Ras, are devoid of a druggable pocket and lack an accessible cysteine for the development of a covalent inhibitor. Here, we report that covalent bond formation by an aryl sulfonyl fluoride electrophile at a tyrosine residue (Tyr-82) inhibits guanine exchange factor Rgl2-mediated nucleotide exchange of Ral GTPase. A high-resolution 1.18-Å X-ray cocrystal structure shows that the compound binds to a well-defined binding site in RalA as a result of a switch II loop conformational change. The structure, along with additional high-resolution crystal structures of several analogs in complex with RalA, confirm the importance of key hydrogen bond anchors between compound sulfone oxygen atoms and Ral backbone nitrogen atoms. Our discovery of a pocket with features found on known druggable sites and covalent modification of a bystander tyrosine residue present in Ral and Ras GTPases provide a strategy that could lead to therapeutic agent targeting oncogenic Ras mutants that are devoid of a cysteine nucleophile.
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