Allosteric inhibitors of liver pyruvate kinase for the treatment of NAFLD

Non-alcoholic fatty liver disease (NAFLD) is defined as hepatic fat accumulation that exceeds 5% of liver weight. Accumulation of lipids in the liver in NAFLD plays a key role in the progression of cirrhosis and hepatocellular carcinoma, a hard-to-treat cancer and it is becoming the major reason for liver transplantation in the world. NAFLD is associated with obesity, type 2 diabetes and metabolic syndrome and estimated 25% of adults worldwide suffer from it. No effective treatment, apart from a significant change in lifestyle, exists for NAFLD. We propose to develop a drug that will reduce the production of lipids in the liver and thereby stop and reverse the progression of the disease. Our drug target is pyruvate kinase, an enzyme that is critical for lipid synthesis. We will improve our early inhibitors to be more potent and specific and thereby pave the way for the first pharmacological treatment for NAFLD.