Development of Small Molecules MAP3K2/3 Inhibitor for Treatment of Acute Lung Injury

Project Summary Abstract Acute lung injuryALIor Acute Respiratory Acute Respiratory Distress SyndromeARDSare characterized by an increased permeability of the alveolar capillary barrier resulting in lung edema with protein rich fluidthus resulting in impairment of arterial oxygenationLung edemaendothelial and epithelial injury are accompanied by an influx of neutrophils into the interstitium and bronchoalveolar spaceThe incidence of ALI ARDS is highper year in the USand the overall mortality remains very highup toDespite all innovations in intensive care medicineThere are currently no effective pharmacological interventions for this devastated diseaseThere is a clear unmet medical need that urgently call for a novel treatment targets and agentsALI can be triggered by multiple direct or indirect environmental causessuch as pneumoniadrowningsepsispancreatitistrauma and reperfusion injuryReperfusion injuryalso known as primary graft dysfunctionPGDis a severe form of ALI that is a major cause of early morbidity and mortality encountered after lung transplantationPGD is diagnosed by pulmonary edema with diffused alveolar damage that manifests clinically as progressive hypoxemia with radiographic pulmonary infiltratesthere are no FDA approved drugs for PGD after lung transplantation to dateWe have discovered the inhibition of Mitogen Activated Protein Kinase Kinase KinaseMAP Kandreduces pulmonary edema and mortality in two mouse ALI models through a highly novel mechanism of actionGenetic loss of MAP Kin myeloid cells and MAP Kin hematopoietic cellsDKOprotects mice from pulmonary edema and death in ALI modelsMore importantlywe discovered that an FDA approved oncology drug pazopanib potently inhibited MAP Kand could recapitulate the phenotypes of MAP Kdeficiency both in vitro and in vivoincluding those in the ALI modelsTogether with human relevant evidencewe believe that pazopanib can be repurposed for treatment of ALI ARDSIn this SBIR Phaseprojectwe aimed to develop new formulation of pazopanib and provide proof of concept and dose dependence response in a mice ALI modelThere aremain objectives for this SBIR PhaseprojectTo identify a new IV formulation of pazopanibwhich will be suitable for animal models and human clinical trialsTo demonstrate desire PK profile andefficacy in the mouse ALI PD model in a dose dependent mannerThe desirable outcome of this SBIR Phaseproject will provide critical data to warrant a SBIR Phaseprojectwhich will focus on Pre IND enabling studies toward human clinical trials Project Narrative The objective of this SBIR phase I project is to develop small molecule MAP KInhibitors for the treatment of Acute Lung InjuryALI