PF-06424439

PF-06424439 is a potent, highly selective, and orally bioavailable small molecule inhibitor of diacylglycerol acyltransferase 2 (DGAT2). Developed by Pfizer, it belongs to the imidazopyridine chemical class and was identified as a preclinical candidate for the treatment of metabolic disorders. DGAT2 is a membrane-bound enzyme that catalyzes the final and rate-limiting step in the synthesis of triacylglycerols (TAGs). PF-06424439 functions as a long residence time, slowly reversible, and noncompetitive inhibitor with respect to the acyl-CoA substrate. Mechanistically, it binds to the enzyme in a two-step process, forming a high-affinity complex that effectively reduces hepatic and circulating lipid levels. Beyond its primary application in hyperlipidemia and hepatic steatosis (NAFLD/NASH), research has explored its role in oncology, where it may sensitize breast cancer cells to nutritional stress or radiation by impairing lipid droplet biogenesis.