4.6 Article

Small molecule targeting of the STAT5/6 Src homology 2 (SH2) domains to inhibit allergic airway disease

Journal

JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 293, Issue 26, Pages 10026-10040

Publisher

AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA117.000567

Keywords

asthma; STAT transcription factor; allergen; fungi; cytokine; peptidomimetic; SH2 domain; STAT5; STAT6

Funding

  1. National Institutes of Health [R41AI25007, R01 HL117181]
  2. Veterans Affairs Office of Research and Development [I01BX002221, I01 CX001673]
  3. American Asthma Foundation
  4. Biology of Inflammation Center, Baylor College of Medicine

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Asthma is a chronic inflammatory disease of the lungs and airways and one of the most burdensome of all chronic maladies. Previous studies have established that expression of experimental and human asthma requires the IL-4/IL-13/IL-4 receptor (IL-4R) signaling pathway, which activates the transcription factor STAT6. However, no small molecules targeting this important pathway are currently in clinical development. To this end, using a preclinical asthma model, we sought to develop and test a small-molecule inhibitor of the Src homology 2 domains in mouse and human STAT6. We previously developed multiple peptidomimetic compounds on the basis of blocking the docking site of STAT6 to IL-4R and phosphorylation of Tyr(641) in STAT6. Here, we expanded the scope of our initial in vitro structure-activity relationship studies to include central and C-terminal analogs of these peptides to develop a lead compound, PM-43I. Conducting initial dose range, toxicity, and pharmacokinetic experiments with PM-43I, we found that it potently inhibits both STAT5- and STAT6-dependent allergic airway disease in mice. Moreover, PM-43I reversed preexisting allergic airway disease in mice with a minimum ED50 of 0.25 g/kg. Of note, PM-43I was efficiently cleared through the kidneys with no long-term toxicity. We conclude that PM-43I represents the first of a class of small molecules that may be suitable for further clinical development against asthma.

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