TGFb1 Receptor 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 the same 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. The cytokine TGF?1 plays a central role in stellate cell activation and fibrosis. TGF?1 binds to and activates its receptor (ALK5), which phosphorylates and activates signaling proteins including Smad2, resulting in expression of upregulation of fibrotic marker genes, such as ?SMA. Our long-term goal is the development of small molecule inhibitors of the TGF?1 receptor as potential therapeutics for fibrotic liver disease. The objective of this application is to identify such inhibitors and evaluate them in two clinically relevant animal models of liver fibrosis. Small molecule inhibitors of the TGF?1 receptor are potential therapeutics for fibrotic disease in the liver, as well as other major organs.