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dc.contributor.authorMandal, Pijus K.
Morlacchi, Pietro
Knight, J. Morgan
Link, Todd M.
Lee, Gilbert R. IV
Nurieva, Roza
Singh, Divyendu
Dhanik, Ankur
Kavraki, Lydia
Corry, David B.
Ladbury, John E.
McMurray, John S.
dc.date.accessioned 2017-05-12T17:10:13Z
dc.date.available 2017-05-12T17:10:13Z
dc.date.issued 2015
dc.identifier.citation Mandal, 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." Journal of Medicinal Chemistry, 58, no. 22 (2015) American Chemical Society: 8970-8984. http://dx.doi.org/10.1021/acs.jmedchem.5b01321.
dc.identifier.urihttps://hdl.handle.net/1911/94247
dc.description.abstract Signal 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.
dc.language.iso eng
dc.publisher American Chemical Society
dc.rights This is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by the American Chemical Society.
dc.title 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
dc.type Journal article
dc.citation.journalTitle Journal of Medicinal Chemistry
dc.citation.volumeNumber 58
dc.citation.issueNumber 22
dc.type.dcmi Text
dc.identifier.doihttp://dx.doi.org/10.1021/acs.jmedchem.5b01321
dc.identifier.pmcid PMC5109833
dc.identifier.pmid 26506089
dc.type.publication post-print
dc.citation.firstpage 8970
dc.citation.lastpage 8984


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