Targeting the Src Homology 2 (SH2) Domain of Signal Transducer and Activator of Transcription 6 (STAT6) with Cell-Permeable, Phosphatase-Stable Phosphopeptide Mimics Potently Inhibits Tyr641 Phosphorylation and Transcriptional Activity

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dc.citation.firstpage8970en_US
dc.citation.issueNumber22en_US
dc.citation.journalTitleJournal of Medicinal Chemistryen_US
dc.citation.lastpage8984en_US
dc.citation.volumeNumber58en_US
dc.contributor.authorMandal, Pijus K.en_US
dc.contributor.authorMorlacchi, Pietroen_US
dc.contributor.authorKnight, J. Morganen_US
dc.contributor.authorLink, Todd M.en_US
dc.contributor.authorLee, Gilbert R. IVen_US
dc.contributor.authorNurieva, Rozaen_US
dc.contributor.authorSingh, Divyenduen_US
dc.contributor.authorDhanik, Ankuren_US
dc.contributor.authorKavraki, Lydiaen_US
dc.contributor.authorCorry, David B.en_US
dc.contributor.authorLadbury, John E.en_US
dc.contributor.authorMcMurray, John S.en_US
dc.date.accessioned2017-05-12T17:10:13Zen_US
dc.date.available2017-05-12T17:10:13Zen_US
dc.date.issued2015en_US
dc.description.abstractSignal transducer and activator of transcription 6 (STAT6) transmits signals from cytokines IL-4 and IL-13 and is activated in allergic airway disease. We are developing phosphopeptide mimetics targeting the SH2 domain of STAT6 to block recruitment to phosphotyrosine residues on IL-4 or IL-13 receptors and subsequent Tyr641 phosphorylation to inhibit the expression of genes contributing to asthma. Structure–affinity relationship studies showed that phosphopeptides based on Tyr631 from IL-4Rα bind with weak affinity to STAT6, whereas replacing the pY+3 residue with simple aryl and alkyl amides resulted in affinities in the mid to low nM range. A set of phosphatase-stable, cell-permeable prodrug analogues inhibited cytokine-stimulated STAT6 phosphorylation in both Beas-2B human airway cells and primary mouse T-lymphocytes at concentrations as low as 100 nM. IL-13-stimulated expression of CCL26 (eotaxin-3) was inhibited in a dose-dependent manner, demonstrating that targeting the SH2 domain blocks both phosphorylation and transcriptional activity of STAT6.en_US
dc.identifier.citationMandal, Pijus K., Morlacchi, Pietro, Knight, J. Morgan, et al.. "Targeting the Src Homology 2 (SH2) Domain of Signal Transducer and Activator of Transcription 6 (STAT6) with Cell-Permeable, Phosphatase-Stable Phosphopeptide Mimics Potently Inhibits Tyr641 Phosphorylation and Transcriptional Activity." <i>Journal of Medicinal Chemistry,</i> 58, no. 22 (2015) American Chemical Society: 8970-8984. http://dx.doi.org/10.1021/acs.jmedchem.5b01321.en_US
dc.identifier.doihttp://dx.doi.org/10.1021/acs.jmedchem.5b01321en_US
dc.identifier.urihttps://hdl.handle.net/1911/94247en_US
dc.language.isoengen_US
dc.publisherAmerican Chemical Societyen_US
dc.rightsThis is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by the American Chemical Society.en_US
dc.titleTargeting the Src Homology 2 (SH2) Domain of Signal Transducer and Activator of Transcription 6 (STAT6) with Cell-Permeable, Phosphatase-Stable Phosphopeptide Mimics Potently Inhibits Tyr641 Phosphorylation and Transcriptional Activityen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpost-printen_US
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