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dc.contributor.authorAtatreh, Noor
dc.contributor.authorBarraclough, Jane
dc.contributor.authorWelman, Arkadiusz
dc.contributor.authorCawthorne, Christopher
dc.contributor.authorBryce, Richard A
dc.contributor.authorDive, Caroline
dc.contributor.authorFreeman, Sally
dc.date.accessioned2009-06-12T14:47:05Z
dc.date.available2009-06-12T14:47:05Z
dc.date.issued2007-10
dc.identifier.citationDifluoro analogue of UCS15A triggers activation of exogenously expressed c-Src in HCT 116 human colorectal carcinoma cells. 2007, 22 (5):638-46 J Enzyme Inhib Med Chemen
dc.identifier.issn1475-6366
dc.identifier.pmid18035832
dc.identifier.doi10.1080/14756360701485760
dc.identifier.urihttp://hdl.handle.net/10541/70332
dc.description.abstractUCS 15A, an antibiotic produced by Streptomyces sp., has been reported to specifically disrupt SH3 domain-mediated interactions in eukaryotic cells. Interestingly, in the case of the non-receptor tyrosine kinase Src, UCS15A was effective in suppressing the SH3 domain-mediated intermolecular rather than intramolecular interactions, and thus prevented Src interactions with certain downstream effectors without affecting Src kinase activity. Here the synthesis of a novel difluoro analogue of UCS15A is described. The effects of this compound (8) on Src activity were tested in HCT 116 colorectal carcinoma cells engineered for inducible expression of c-Src. The presence of compound (8) resulted in the increased activity of the induced c-Src implicating that (8) acts as a c-Src activator in vivo. These observations are supported by computer modelling studies which suggest that the aldehyde group of (8) may covalently bind to a lysine residue in the SH2-kinase linker region situated in the proximity of the SH3 domain, which could promote a conformational change resulting in increased Src activity.
dc.language.isoenen
dc.subjectCell Line Tumouren
dc.subjectColorectal Canceren
dc.subject.meshBenzaldehydes
dc.subject.meshCarcinoma
dc.subject.meshCell Line, Tumor
dc.subject.meshColorectal Neoplasms
dc.subject.meshComputer Simulation
dc.subject.meshEnzyme Activation
dc.subject.meshEnzyme Activators
dc.subject.meshFluorine
dc.subject.meshHumans
dc.subject.meshModels, Biological
dc.subject.meshMolecular Structure
dc.subject.meshProtein Conformation
dc.subject.mesho-Phthalaldehyde
dc.subject.meshsrc-Family Kinases
dc.titleDifluoro analogue of UCS15A triggers activation of exogenously expressed c-Src in HCT 116 human colorectal carcinoma cells.en
dc.typeArticleen
dc.contributor.departmentSchool of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M13 9PT, UK.en
dc.identifier.journalJournal of Enzyme Inhibition and Medicinal Chemistryen
html.description.abstractUCS 15A, an antibiotic produced by Streptomyces sp., has been reported to specifically disrupt SH3 domain-mediated interactions in eukaryotic cells. Interestingly, in the case of the non-receptor tyrosine kinase Src, UCS15A was effective in suppressing the SH3 domain-mediated intermolecular rather than intramolecular interactions, and thus prevented Src interactions with certain downstream effectors without affecting Src kinase activity. Here the synthesis of a novel difluoro analogue of UCS15A is described. The effects of this compound (8) on Src activity were tested in HCT 116 colorectal carcinoma cells engineered for inducible expression of c-Src. The presence of compound (8) resulted in the increased activity of the induced c-Src implicating that (8) acts as a c-Src activator in vivo. These observations are supported by computer modelling studies which suggest that the aldehyde group of (8) may covalently bind to a lysine residue in the SH2-kinase linker region situated in the proximity of the SH3 domain, which could promote a conformational change resulting in increased Src activity.


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