STAT Inhibitors for Asthma Therapy - Asthma, a chronic disease of the lungs that affects adults and children of all ages, has markedly increased in incidence, prevalence and severity over the past several decades with a prevalence of 8.4% in the U.S. The current standard of care for asthma consists of the combination of long acting beta2 adrenergic receptor agonists, which relieve airway constriction, and glucocorticosteroids, which reduce airway inflammation. While this treatment is initially effective, resistance to therapy as well as excess asthma-related mortality and other serious adverse effects related to glucocorticosteroids remain serious and ongoing problems deserving of improved approaches. Asthma patients have elevated levels of the cytokines IL-4 and IL-13 in their airways, which result in mucus production, airway hyperresponsiveness to acetylcholine (AHR), eosinophil recruitment, helper T cell 2 (TH2) activation, immunoglobulin class switching to IgE, and inflammation. These two cytokines signal through IL-4Ralpha and activate JAK1, JAK3, or Tyk2 which leads to phosphorylation of the signal transducer and activator of transcription 6 (STAT6). pSTAT6 then dimerizes via reciprocal SH2 domain-pTyr641 interactions, translocates to the nucleus, and participates in the expression of genes leading to asthma. Importantly, pSTAT6 levels are elevated in the bronchial epithelium of asthma patients and STAT6 knockout mice do not develop AHR or lung pathology associated with asthma. Taken together, these studies support the hypothesis that inhibiting the activity of STAT6 is a potential modality for asthma treatment. Atrapos, LLC is a privately-held preclinical stage therapeutics company dedicated to the advancement of innovative therapies for asthma. Atropos’ innovation is the direct result of basic research conducted by Atropos co-founders Drs. John McMurray and David Corry. Our lead molecule, PM-43I, is a small-molecule, cell-permeable, and phosphatase-stable phosphopeptide mimetic that targets the SH2 domain of STAT6 and prevents recruitment to IL-4Ralpha and the subsequent transcriptional activity leading to the asthma phenotype. Our in vivo experiments demonstrate that PM-43I prevents the induction of fungal-induced asthma and, more importantly, reverses many of the hallmark features of asthma including airway constriction, lung inflammation, and lung mucus production. The focus of this proposal is to accomplish key milestones that will further transition this technology for commercialization for the asthma market by measuring absorption from the lung, distribution to other tissues, metabolism and elimination and potential toxicity of the molecule. The project is organized into two measureable Specific Aims: 1. Characterize the pharmacokinetic profile of PM-43I and 2. Assess potential toxicities of PM-43I.
