Structurally engineered N-acyl amino acids for the treatment of NASH

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Project Summary Nonalcoholic steatohepatitis (NASH) occurs when excessive amounts of fat build up in the liver, damaging hepatocytes and causing inflammation. The progression of the disease further leads to fibrosis, hepatocellular carcinoma, and liver failure. After numerous failures in clinical trials with single-agent therapies, the therapeutic approach has gradually shifted toward using combination therapies that involve both a metabolic modifier and an anti-fibrotic agent. However, limited progress has been made so far. We recently discovered that not only lipid metabolism but also amino acid metabolism is disrupted in NASH, leading to the development of fatty acid- amino acid conjugates (NAAs) intersecting both metabolic pathways for the treatment of NASH. Mice with established NASH that were treated with endogenous NAAs exhibited reduced steatohepatitis and fibrosis. Using a medicinal chemistry approach, we designed, synthesized, tested, and optimized a series of novel NAAs. Our current lead compound, FAL-113, obtained superior physicochemical properties, oral bioavailability, and efficacy in preliminary cellular and animal models. It is hypothesized that FAL-113 could reduce lipotoxicity by simultaneously increasing fatty acid oxidation and decreasing its biosynthesis while providing the anti-fibrosis seen with the endogenous NAAs. In addition, the novel structural modification improved the compound’s oral bioavailability and half-life, enabling an otherwise impossible oral administration. The metabolism of FAL-113 also releases a secondary bioactive fatty acid that improves energy homeostasis through metabolic reprogramming, which subsequently benefits the comorbidities commonly associated with NASH. The greatly improved pharmacokinetics and efficacy of novel NAAs led us to hypothesize that FAL-113 could tackle NASH through a multiplexed mechanism – synergizing the benefits of metabolic modification and anti- inflammatory/fibrotic properties. This hypothesis will be tested by pursuing the following Specific Aims: Aim 1: Determine the mechanisms of action of FAL-113 using bioorthogonal chemistry. Aim 2: Establish the pharmacokinetics of FAL-113 in rodents. Aim 3: Define the pharmacology of FAL-113 in a NASH mouse model. The multidisciplinary approach involved in the project, including bioorthogonal chemistry, mass spectrometer- based analytics, and animal pharmacokinetics and pharmacology, will definitively reveal the ADME, validate the protection against NASH and characterize the modes of action of the lead compound FAL-113. The successful outcomes of this project will result in a solid preclinical candidate ready for IND-enabling studies and greatly accelerate its translation to real clinical value for NASH patients. The team leading this effort has experienced and participated in several preclinical and clinical studies in related disease areas. In addition, the team is supported by experienced collaborators and consultants to execute the proposed research plan successfully.