Small molecule antagonists targeting EphB receptors for the treatment of nonalcoholic steatohepatitis (NASH)

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Project Summary Non-alcoholic steatohepatitis (NASH) is an asymptomatic, multifactorial, chronic liver fibrotic disease that drastically impairs hepatic function and affects a large proportion of the US population. NASH is caused by a diet-related fattening of the liver that progresses with inflammation, hepatocyte degeneration, and a pro-fibrotic response that ultimately results in cirrhosis and liver failure. There are no FDA-approved treatments for NASH and the only options for disease management are changes in lifestyle, bariatric surgery, or liver transplantation. The need for therapeutic measures to combat NASH is thus enormous, especially considering that the number of patients diagnosed worldwide is increasing dramatically due to the growing epidemic of obesity and diabetes. This proposal identifies the EphB receptor tyrosine kinases and their transmembrane EphrinB ligands as molecules to target for the treatment of NASH. Cell-cell interactions of EphB receptors with EphrinB ligands initiates bidirectional signaling cascades that can affect diverse biological processes relevant to NASH fibrogenesis including cellular remodelling, angiogenesis, migration/proliferation, epithelial-to-mesenchymal- transition, and inflammation. The long-term goal of this project is to develop a potent inhibitor of EphB/EphrinB signaling for the treatment of NASH. We will leverage our early work that shows EphB2 promotes hepatic inflammation and fibrosis in mice with our recent discovery of a potent small molecule EphB/EphrinB receptor- ligand chemical antagonist/inhibitor. The objective of this application is to optimize our prototype lead compound to maximize its inhibitory and pharmacological properties for the treatment of NASH. Using in vitro assays, our preliminary data indicates the prototype lead compound reduces TGF-β1-driven trans- differentiation of primary human hepatic stellate cells into pro-fibrotic myofibroblasts, a process known to contribute to liver fibrosis in NASH. Furthermore, early tests of our lead compound in vivo indicates it reduces steatosis, inflammation, and fibrosis in clinically relevant NASH mouse models. Guided by strong early-stage preclinical data on the efficacy of our prototype lead compound to resolve liver fibrosis and metabolic dysfunction associated with NASH, Aim 1 will focus on medicinal chemistry efforts to better understand the structure activity relationship of our lead compound and to identify and characterize more potent related analog chemicals that exhibit improved antagonist activity and drug-like pharmacological properties. In Aim 2 we will test and validate the efficacy of our lead compound and the resulting new and improved analogs for their ability to reverse liver fibrosis and metabolic dysfunction in established NASH models. To the best of our knowledge, this work is the first to investigate the therapeutic potential of targeting EphB/EphrinB signalling for the treatment of NASH. The proposed research is highly significant because it will advance for the treatment of NASH novel compounds that target a signaling axis not currently in the interest or forefront of the biotechnology and pharmaceutical industries.