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

Abstract

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 α (IL-4Rα) 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-4Rα and phosphorylation of Tyr in STAT6. Here, we expanded the scope of our initial 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 ED of 0.25 μg/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.

Pancreatic progenitor cell differentiation and proliferation factor predicts poor prognosis in heptaocellular carcinoma

“…The former SH domains are considered associating with proteins of signaling pathways involving in the cytoskeleton, the Ras associated protein, and many others. [11] The CLK2 kinase has shown to interact with serine/arginine-rich (SR) proteins of the spliceosomal complex, which is responsible for the SR proteins to control RNA splicing. [12] This protein kinase is involved in the regulation of several cellular processes and may serve as a link between cell cycle progression, apoptosis, and telomere length regulation.…”

STAT6 Blockade Abrogates Aspergillus-Induced Eosinophilic Chronic Rhinosinusitis and Asthma, A Model of Unified Airway Disease

“…A critical task suggested by our analyses is determining the essential inflammatory pathways that drive eosinophilic inflammation of both the upper and lower airways during airway mycosis. STAT6 has previously been shown to drive eosinophilic lower airway inflammation under a variety of short-term inflammatory challenge conditions, including fungal ( 10 ). Utilizing STAT6-deficient mice, we found that challenge of mice with A. niger over 12 weeks resulted in a similarly marked reduction in lung eosinophils as assessed by flow cytometry, but we also found near-complete suppression of all other inflammatory cells including macrophages, neutrophils, and T cells ( Figure 7A ).…”

“…The STAT6 inhibitor is formulated in liposomes with 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC; 850335, Avanti Polar Lipids) as previously described ( 10 ). Prior to formulating daily treatments, vehicle and drug suspensions were briefly sonicated for 30 s and vortexed.…”

“…Although efficacious for both asthma and CRS, dupilumab and other biologics are expensive (ranging from $10,000 to $40,000 per year) and noncurative. The efficacy of dupilumab in the treatment of severe allergic asthma and CRS and studies in STAT6-deficient mice highlight the central role of the IL4/IL13-IL4Ra-STAT6 signaling pathway in developing eosinophilic asthma (8)(9)(10). Additionally, our group has pioneered the emerging paradigm that fungi are fundamental causes of both asthma and CRS (4,5,11) through the elaboration of key virulence factors such as proteinases (12), cytokines [cleaved fibrinogen (13,14)], and candidalysin (15).…”

“…Moreover, mimetic peptides targeting the SH2 domain of STAT6 have been developed that block the function of both STAT5 and STAT6 ( 17 ). These aerosolized small-molecule inhibitors, which minimize systemic adverse effects, not only inhibited the development, but also reversed airway mycosis-dependent allergic lung disease in preclinical allergic airway disease ( 10 ). Given the lack of a widely accepted mouse model for CRS, the utility of these promising small peptide inhibitors and other potential therapeutics has not been adequately evaluated for chronic eosinophilic sinus inflammation.…”