PDGFR and KDR Inhibitors for Liver Fibrosis

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DESCRIPTION (provided by applicant): Liver fibrosis, a disease affecting tens of millions of patients worldwide, is the liver scarring response to chronic injury from viral hepatitis B or C, excessive alcohol use, iron overload or extrahepatic obstructions and can progress to liver cirrhosis, liver failure and death. In fact, deaths from complications of liver fibrosis/cirrhosis are expected to triple over the next decade as a result of the hepatitis C epidemic and the growing incidence of liver disease associated with non-alcoholic steatohepatitis. Currently available therapies, including antivirals, are largely ineffective in treating the underlying fibrosis, and in the majority of cases, liver transplantation is the only effective cure. Liver fibrosis, irrespective of its etiology, reflects common cellular and molecular pathophysiology. Activation of hepatic stellate cells and conversion to myofibroblasts is the dominant event in fibrogenesis, and proceeds along a continuum that involves progressive changes in cellular function. Signaling through the platelet-derived growth factor (PDGF) pathway and vascular endothelial growth factor (VEGF) pathway play important roles in liver fibrosis. Angion has identified a small molecule, ANG-3154, that inhibits activation of the PDGF receptor (PDGFR-b) and the (KDR) and their tyrosine kinase activities. Preliminary data also indicate that this compound is antifibrotic in vivo. Our long-term goal is the development of small molecule dual inhibitors of PDGFR-b and KDR as potential therapeutics for fibrotic liver disease as well as fibrotic disease in other organs. The objective of this application is to identify such inhibitors and evaluate them in two clinically relevant animal models of liver fibrosis. PUBLIC HEALTH RELEVANCE: Small molecule dual inhibitors of the PDGFR and KDR receptors are potential therapeutics for fibrotic disease in the liver, as well as other major organs.