Axin Stabilization by Novel Small Molecules to Treat Non-alcoholic Steatohepatitis

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PROJECT SUMMARY/ABSTRACT Non-alcoholic steatohepatitis (NASH) affects 12% of Americans due to the growing number of individuals with metabolic disorders, including nonalcoholic fatty liver disease, obesity, metabolic syndromes, and diabetes. At present, there are no pharmacological options approved for NASH. Wnt/beta-catenin pathway and adenosine monophosphate-activated kinase (AMPK) are crucial pathways in regulation of hepatic metabolism. Genetic and pharmacological evidence supports a benefit by inhibition of Wnt/beta-catenin on hepatic metabolism; meanwhile, AMPK activation has emerged as a mechanism against NASH. We have synthesized and tested a novel class of compounds, of which triazole YW1128 showed dual activities of Wnt/beta-catenin inhibition and AMPK activation via the mechanism of Axin stabilization. YW1128 showed an exciting efficacy against hepatic steatosis both in vitro and in mice. Based on the chemical structure of YW1128, we recently designed and synthesized the new lead YA6060. While maintaining the dual activities, YA6060 has exhibited a highly promising drug-like profile and particularly an exciting efficacy against hepatic steatosis and fibrosis. We also discovered the tankyrase-binding protein 1 (TNKS1bp1 or TAB182) as a binding target of our lead compounds. The proposed studies are intended to test the hypothesis that simultaneously inhibiting Wnt/beta-catenin pathway and activating AMPK, by stabilizing cellular Axin level via targeting TAB182 with small molecules, is a novel therapeutic strategy for NASH treatment. To test this hypothesis, we will first synthesize and evaluate new compounds that inhibit Wnt/β-catenin signaling and activate AMPK, using an iterative process involving new analog design, synthetic chemistry, in vitro assessment of drug properties, and in vivo pharmacokinetic and toxicity evaluation. Second, by conducting in vitro and in vivo experiments including ligand binding assays, genetic knockdown, transgene expression, genetic mutation, chemical inhibition or activation, and various functional assays, we will determine the mechanism of action for lead compounds in hepatocytes and mice. Lastly, we will evaluate the efficacy of YA6060 and a new YA6060-based lead compound and validate their pharmacological mechanism in mouse models with a full range of NASH indications. Successful completion of this project is expected to establish that small molecules with dual activities of Wnt/beta-catenin inhibition and AMPK activation via targeting TAB182 and Axin stabilization is a valid resource for the development of NASH therapeutics. The knowledge and small molecules are expected to greatly benefit future research in understanding of NASH pathogenesis. Eventually, we expect to transform NASH patient care with a first-in-class drug.