ArticleNature chemical biology2024
Strain-release alkylation of Asp12 enables mutant selective targeting of K-Ras-G12D.
Article in Nature chemical biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 66 citations in OpenAlex.
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- Chemical Biology 2025: Highlights From the Ch/Bi145 Course at Caltech.Chembiochem : a European journal of chemical biology · 2026Review
- Brønsted-basic small molecules activate GTP hydrolysis in KRAS-Q61 mutants.Nature chemical biology · 2026Article
- Precision Therapeutics in Pancreatic Cancer: Emerging Targeted, Immune, and Antibody-Drug Conjugate Strategies Exemplified by Adagrasib, Dostarlimab, and Trastuzumab Deruxtecan.Journal of clinical medicine · 2026Review
- Stereoselective Covalent Targeting of BTK(C481S) and Kinases with β-Lactone Electrophiles.bioRxiv : the preprint server for biology · 2026Article
- Structure-Activity Relationship Analysis of Macrocyclic Peptide RAS Inhibitors: Spotlight on the Solvent-Exposed Region.ACS medicinal chemistry letters · 2026Article
- A Global Ligandability Map of Tryptoline Butynamide Stereoprobes Identifies Covalent Inhibitors of the Actin Maturation Protease.Journal of the American Chemical Society · 2026Article
- Single-Sequence Deep Learning Delivers Crystal-Quality Models of Covalent K-Ras G12 Hotspot Complexes.IUBMB life · 2026Article
- Activity of Direct KRAS(G12C) Inhibitors in Preclinical Models of Pediatric Cancer.Molecular cancer therapeutics · 2026Article
- A Global Ligandability Map of Tryptoline Butynamide Stereoprobes Identifies Covalent Inhibitors of the Actin Maturation Protease ACTMAP.bioRxiv : the preprint server for biology · 2026Article
- ZBTB11 depletion targets metabolic vulnerabilities in KRAS inhibitor-resistant PDAC.Nature chemical biology · 2026Article
- Covalent modification of a glutamic acid inspired by HaloTag technology.Nature communications · 2026Article
- Targeting a Glutamic Acid in PDEδ with Fluoromethyl-Aryl Electrophiles Impairs K-Ras Signaling.Journal of medicinal chemistry · 2026Article
- RAS(ON) Multiselective Inhibition Drives Antitumor Immunity in Preclinical Models of NRAS-Mutant Melanoma.Cancer immunology research · 2026Article
- Identification and characterization of binders to a cryptic and functional pocket in KRAS.Nature communications · 2025Article
- Targeting KRAS G12D: Advances in Inhibitor Design.Thoracic cancer · 2025Review
- A Fragment-Based Electrophile-First Approach to Target Histidine with Aryl-Fluorosulfates: Application to hMcl-1.Journal of medicinal chemistry · 2025Article
- Targeting KRASScientific reports · 2025Article
- A Modular Platform for the Optogenetic Control of Small GTPase Activity in Living Cells Reveals Long-Range RhoA Signaling.bioRxiv : the preprint server for biology · 2025Article
- Covalent Ligand Electrophiles Are Differentially Activated by Proximity Effects Which Govern Latent Protein Reactivity.ACS central science · 2025Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
K-Ras is the most commonly mutated oncogene in human cancer. The recently approved non-small cell lung cancer drugs sotorasib and adagrasib covalently capture an acquired cysteine in K-Ras-G12C mutation and lock it in a signaling-incompetent state. However, covalent inhibition of G12D, the most frequent K-Ras mutation particularly prevalent in pancreatic ductal adenocarcinoma, has remained elusive due to the lack of aspartate-targeting chemistry. Here we present a set of malolactone-based electrophiles that exploit ring strain to crosslink K-Ras-G12D at the mutant aspartate to form stable covalent complexes. Structural insights from X-ray crystallography and exploitation of the stereoelectronic requirements for attack of the electrophile allowed development of a substituted malolactone that resisted attack by aqueous buffer but rapidly crosslinked with the aspartate-12 of K-Ras in both GDP and GTP state. The GTP-state targeting allowed effective suppression of downstream signaling, and selective inhibition of K-Ras-G12D-driven cancer cell proliferation in vitro and xenograft growth in mice.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.