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
Morlacchi P.,University of Texas M. D. Anderson Cancer Center |
Link T.M.,Center for Biomolecular Structure and Function |
Link T.M.,University of Texas M. D. Anderson Cancer Center |
Lee G.R.,Center for Biomolecular Structure and Function |
And 7 more authors.
Journal of Medicinal Chemistry | Year: 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 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. © 2015 American Chemical Society.
Bagheri-Yarmand R.,University of Texas M. D. Anderson Cancer Center |
Sinha K.M.,University of Texas M. D. Anderson Cancer Center |
Gururaj A.E.,Center for Biomolecular Structure and Function |
Ahmed Z.,Center for Biomolecular Structure and Function |
And 7 more authors.
Journal of Biological Chemistry | Year: 2015
Background: Activating mutations of the receptor tyrosine kinase RET are associated with oncogenic function in medullary thyroid cancer. Results: RET is a dual specificity kinase phosphorylates ATF4, and inhibits expression of the ATF4 target proapoptotic genes. Conclusion: RET prevents apoptosis through inhibition of ATF4 activity. Significance Simultaneous targeting of RET and ATF4 may provide clinical benefit in cancers with RET abnormalities. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.