Treating Acute Lung Injury via Cytokine Signaling Blockade

DESCRIPTION provided by applicant Acute lung injury ALI and acute respiratory distress syndrome ARDS result from a common pathogenic process pulmonary injury or infection triggers an overwhelming inflammatory response andquot cytokine stormandquot that results in increased endothelial and epithelial permeability and efflux of inflammatory cells protein and water from the vascular system into the alveolar space The incidence of ALI is estimated to be approximately cases per person years The treatment for those afflicted remains largely supportive with a mortality rate of approximately We have demonstrated that the small GTPase Arf is a convergence point in the signaling pathways of several inflammatory mediators and cytokines with demonstrated involvement in ALI ARDS Activation of Arf into its GTP bound state induces vascular leak and edema which play major roles in the pathophysiology of ALI ARDS Thus we hypothesize that pharmacological inhibition of Arf provides an opportunity to combat actions of multiple cytokines in ALI ARDS an approach which may be more effective than targeting single pathways with highly specific inhibitors This rationale is supported by the encouraging preliminary in vivo data generated with our small molecule inhibitor of Arf NAV in a murine model of lipopolysaccharide LPS induced ALI This phase SBIR will improve upon our current NAV series of Arf inhibitors through an in silico molecular modeling effort to identify compounds with improved potency and hydrophilicity We will determine potency in a biochemical nucleotide exchange assay and verify activity in a mechanism based cellular Arf pulldown assay Compounds with an optimal mix of potency and hydrophilicity will be screened in vivo to determine pharmacokinetic PK parameters We will then demonstrate proof of concept efficacy in the murine LPS induced ALI model Successful completion of these activities will accomplish two very important goals First it will provide proof of concept that inhibiting Arf is a promising novel approach for treating ALI ARDS Second it will position us to continue medicinal chemistry optimization of Arf inhibitors in Lead Optimization activities in phase optimization of potency selectivity solubility ADMET properties patentability Successful completion of this development program may result in a therapy effective for treating humans with ALI ARDS PUBLIC HEALTH RELEVANCE Acute lung injury ALI and the more severe acute respiratory distress syndrome ARDS result from a common pathogenic process pulmonary injury or infection triggers an overwhelming inflammatory response andquot cytokine stormandquot that results in increased endothelial and epithelial permeability and efflux of inflammatory cells protein and water from the vascular system into the alveolar space The incidence of ALI is estimated to be approximately cases per person years Treatment for ALI ARDS is primarily supportive care and though there have been improvements in outcomes over the past decade due to improved strategies of mechanical ventilation and advances in general supportive measures the mortality rate of patients with ALI ARDS is approximately