ArticleProceedings of the National Academy of Sciences of the United States of America2012
Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 319 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
319 citing papers in PubMed, 623 citations in OpenAlex.
- Brønsted-basic small molecules activate GTP hydrolysis in KRAS-Q61 mutants.Nature chemical biology · 2026Article
- Unveiling the KRAS Relationship between Affinity and Dynamics: A Molecular Simulations Study.Journal of chemical information and modeling · 2026Article
- Synthesis and Biochemical Characterization of Investigational Pyrazolopyrimidine-Based Allosteric KRAS Modulators.ACS medicinal chemistry letters · 2026Article
- Disulfide tethering reveals cryptic pockets in oncogenic KRAS.Communications chemistry · 2026Article
- Discovery and Characterization of Divarasib (GDC-6036), a Potent Covalent Inhibitor of KRAS G12C.Journal of medicinal chemistry · 2026Article
- Article
- Decoding the Post-translational Modification Crosstalk: Functional Implications of Phosphorylation, Acetylation, and Methylation.The journal of physical chemistry. B · 2026Article
- Clinical management and therapeutic development for the rare disease rhabdomyosarcoma.Journal of Cancer · 2026Review
- The Human Omnibus of Targetable Pockets.Journal of cheminformatics · 2025Article
- Review
- Evolution of direct RAS inhibitors: from undruggable target to clinical breakthroughs.Molecular cancer · 2025Review
- Identification of KRAS mutants (G12C, G12D, and G12V) inhibitors.Future medicinal chemistry · 2025Article
- Discovery of BI-2493, a Pan-KRAS Inhibitor ShowingJournal of medicinal chemistry · 2025Article
- ADMET-Guided Docking and GROMACS Molecular Dynamics ofPharmaceuticals (Basel, Switzerland) · 2025Article
- Methods for Controlling Small GTPase Activity.Chembiochem : a European journal of chemical biology · 2025Review
- The complex journey of targeting RAS in oncology.BMC cancer · 2025Review
- Switching It up with New KRAS Inhibitors.Journal of medicinal chemistry · 2025Review
- Glecirasib, a Potent and Selective Covalent KRAS G12C Inhibitor Exhibiting Synergism with Cetuximab or SHP2 Inhibitor JAB-3312.Cancer research communications · 2025Article
- Article
- Evolution of computational techniques against various KRAS mutants in search for therapeutic drugs: a review article.Cancer chemotherapy and pharmacology · 2025Review
259 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
20 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The Ras gene is frequently mutated in cancer, and mutant Ras drives tumorigenesis. Although Ras is a central oncogene, small molecules that bind to Ras in a well-defined manner and exert inhibitory effects have not been uncovered to date. Through an NMR-based fragment screen, we identified a group of small molecules that all bind to a common site on Ras. High-resolution cocrystal structures delineated a unique ligand-binding pocket on the Ras protein that is adjacent to the switch I/II regions and can be expanded upon compound binding. Structure analysis predicts that compound-binding interferes with the Ras/SOS interactions. Indeed, selected compounds inhibit SOS-mediated nucleotide exchange and prevent Ras activation by blocking the formation of intermediates of the exchange reaction. The discovery of a small-molecule binding pocket on Ras with functional significance provides a new direction in the search of therapeutically effective inhibitors of the Ras oncoprotein.
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Registered trials
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.