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    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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    Mandal, Pijus K.; Morlacchi, Pietro; Knight, J. Morgan; Link, Todd M.; Lee, Gilbert R. IV; More... Nurieva, Roza; Singh, Divyendu; Dhanik, Ankur; Kavraki, Lydia; Corry, David B.; Ladbury, John E.; McMurray, John S. Less...
    Date
    2015
    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.
    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.
    Published Version
    http://dx.doi.org/10.1021/acs.jmedchem.5b01321
    Type
    Journal article
    Publisher
    American Chemical Society
    Citable link to this page
    https://hdl.handle.net/1911/94247
    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.
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    • Computer Science Publications [148]
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    Home | FAQ | Contact Us | Privacy Notice | Accessibility Statement
    Managed by the Digital Scholarship Services at Fondren Library, Rice University
    Physical Address: 6100 Main Street, Houston, Texas 77005
    Mailing Address: MS-44, P.O.BOX 1892, Houston, Texas 77251-1892
    Site Map