Development of Small Molecule Mimetics of hepatocyte Growth Factor (HGF)

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DESCRIPTION (provided by applicant): The naturally-occurring cytokine hepatocyte growth factor (HGF), also known as scatter factor(SF), is active in numerous tissues throughout the body, participating in the regulation of angiogenesis, organogenesis, tissue repair and neural induction. HGF is 1) mitogenic in many normal cell types, including hepatocytes, vascular endothelial cells, and melanocytes; 2) a morphogen that promotes the formation of branched tube-like structures in epithelial cells; 3) cytoprotective by virtue of its anti-apoptotic activity and exerts anti-fibrotic effects by opposing TGFbeta1-Smad signaling. All biological effects of HGF are triggered by stimulating its cell surface receptor c-Met, with concomitant activation of downstream effector pathways. Several recently published studies have documented the therapeutic potential of exogenously administered SF/HGF in animal models of renal, pulmonary and liver fibrosis. Administration of HGF into injured liver tissue suggests that the cytokine is effective in promoting tissue repair and organ regeneration and in reducing fibrosis. HGF effectively alleviates the structural damage seen in liver cirrhosis, an end-stage liver disease that is frequently caused by Hepatitis C infection or long-term alcohol abuse. Given it's therapeutic potential, there is heightened interest in the development of HGF mimetics that can activate c-Met. To date, an HGF-derived peptide and c-Met activating antibodies have been developed, yet those polypeptide-based mimetics are unstable and expensive. To overcome these shortcomings, we will develop small molecule mimetics of HGF activity. In Aim 1, we will design such small molecules using our LRD (Limited rational design) approach and synthesize them using synthetic organic technology. In aim 2, we will test the activity of our newly developed compounds in epithelial cell culture models. PUBLIC HEALTH RELEVANCE: Administration of Hepatocyte Growth Factor (HGF), a naturally occurring cytokine, has proven beneficial for the recovery from liver injury during hepatitis infection and during liver transplantation in animal models. It is also the only efficient treatment for chronic liver disease (cirrhosis) that causes a scarring of the liver and steady decline of its function. Cirrhosis is most often caused by Hepatitis C infection and long-term alcohol abuse. However, HGF production is expensive and the manufactured protein is not stable, making it unsuitable for therapeutic use. To circumvent these problems, we will develop small molecule mimetics of HGF that work with equal or better efficacy and specificity and are cheaper to produce and easier to administer than recombinantly made HGF.