P. K. Mandal, P. Morlacchi, J. M. Knight, T. M. Link, G. R. Lee, R. Nurieva, D. Singh, A. Dhanik, L. E. Kavraki, D. B. Corry, J. E. Ladbury, and J. S. McMurray, “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, 2015.
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 analogs 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.