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

Pijus K. Mandal, Pietro Morlacchi, J. Morgan Knight, Todd M. Link, Gilbert R. Lee, Roza Nurieva, Divyendu Singh, Ankur Dhanik, Lydia Kavraki, David B. Corry, John E. Ladbury, John S. McMurray

Research output: Contribution to journalArticle

23 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)8970-8984
Number of pages15
JournalJournal of Medicinal Chemistry
Volume58
Issue number22
DOIs
StatePublished - Nov 25 2015

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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