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 in the U S The current standard of care for asthma consists of the combination of long acting beta 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 and IL in their airways which result in mucus production airway hyperresponsiveness to acetylcholine AHR eosinophil recruitment helper T cell TH activation immunoglobulin class switching to IgE and inflammation These two cytokines signal through IL Ralpha and activate JAK JAK or Tyk which leads to phosphorylation of the signal transducer and activator of transcription STAT pSTAT then dimerizes via reciprocal SH domain pTyr interactions translocates to the nucleus and participates in the expression of genes leading to asthma Importantly pSTAT levels are elevated in the bronchial epithelium of asthma patients and STAT knockout mice do not develop AHR or lung pathology associated with asthma Taken together these studies support the hypothesis that inhibiting the activity of STAT 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 I is a small molecule cell permeable and phosphatase stable phosphopeptide mimetic that targets the SH domain of STAT and prevents recruitment to IL Ralpha and the subsequent transcriptional activity leading to the asthma phenotype Our in vivo experiments demonstrate that PM I 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 Characterize the pharmacokinetic profile of PM I and Assess potential toxicities of PM I Project Narrative Allergic disease such as asthma and allergies are among the most common chronic diseases of humans and improved therapies are clearly needed We have developed a new class of drug that potently relieves the symptoms of asthma In this study we will obtain a more detailed understanding of the toxicology and drug disposition of our lead drug candidate