Mandal, Pijus K.Morlacchi, PietroKnight, J. MorganLink, Todd M.Lee, Gilbert R. IVNurieva, RozaSingh, DivyenduDhanik, AnkurKavraki, LydiaCorry, David B.Ladbury, John E.McMurray, John S.2017-05-122017-05-122015Mandal, 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.https://hdl.handle.net/1911/94247Signal 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.engThis is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by the American Chemical Society.Journal articlehttp://dx.doi.org/10.1021/acs.jmedchem.5b01321