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

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.