Discovery and characterization of small molecules that target the Ral GTPase

dc.contributor.authorYan, Chao
dc.contributor.authorLiu, Degang
dc.contributor.authorLi, Liwei
dc.contributor.authorWempe, Michael F.
dc.contributor.authorGuin, Sunny
dc.contributor.authorKhanna, May
dc.contributor.authorMeier, Jeremy
dc.contributor.authorHoffman, Brenton
dc.contributor.authorOwens, Charles
dc.contributor.authorWysoczynski, Christina L.
dc.contributor.authorNitz, Matthew D.
dc.contributor.authorKnabe, Eric W.
dc.contributor.authorBrautigan, David L.
dc.contributor.authorPaschal, Bryce M.
dc.contributor.authorSchwartz, Martin A.
dc.contributor.authorJones, David
dc.contributor.authorRoss, David
dc.contributor.authorMeroueh, Samy O.
dc.contributor.authorTheodorescu, Dan
dc.contributor.departmentDepartment of Biochemistry & Molecular Biology, IU School of Medicineen_US
dc.date.accessioned2016-03-14T22:15:36Z
dc.date.available2016-03-14T22:15:36Z
dc.date.issued2014-11-20
dc.description.abstractThe Ras-like GTPases RalA and B are important drivers of tumor growth and metastasis. Chemicals that block Ral function would be valuable as research tools and for cancer therapeutics. Here, we used protein structure analysis and virtual screening to identify drug-like molecules that bind a site on the GDP-form of Ral. Compounds RBC6, RBC8 and RBC10 inhibited Ral binding to its effector RalBP1, Ral-mediated cell spreading in murine fibroblasts and anchorage-independent growth of human cancer cell lines. Binding of RBC8 derivative BQU57 to RalB was confirmed by isothermal titration calorimetry, surface plasma resonance and 15N-HSQC NMR. RBC8 and BQU57 show selectivity for Ral relative to Ras or Rho and inhibit xenograft tumor growth similar to depletion of Ral by siRNA. Our results show the utility of structure-based discovery for development of therapeutics for Ral-dependent cancers.en_US
dc.eprint.versionAuthor's manuscripten_US
dc.identifier.citationYan, C., Liu, D., Li, L., Wempe, M. F., Guin, S., Khanna, M., … Theodorescu, D. (2014). Discovery and characterization of small molecules that target the Ral GTPase. Nature, 515(7527), 443–447. http://doi.org/10.1038/nature13713en_US
dc.identifier.issn0028-0836en_US
dc.identifier.urihttps://hdl.handle.net/1805/8846
dc.language.isoen_USen_US
dc.publisherNature Publishing Groupen_US
dc.relation.isversionof10.1038/nature13713en_US
dc.relation.journalNatureen_US
dc.rightsPublisher Policyen_US
dc.sourcePMCen_US
dc.subjectDrug Screening Assays, Antitumoren_US
dc.subjectMolecular Targeted Therapyen_US
dc.subjectSmall Molecule Librariesen_US
dc.subjectchemistryen_US
dc.subjectpharmacologyen_US
dc.subjectral GTP-Binding Proteinsen_US
dc.subjectantagonists & inhibitorsen_US
dc.titleDiscovery and characterization of small molecules that target the Ral GTPaseen_US
dc.typeArticleen_US
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