Development of the novel ACLY inhibitor 326E as a promising treatment for hypercholesterolemia.

Hepatic cholesterol accumulation is an important contributor to hypercholesterolemia, which results in atherosclerosis and cardiovascular disease (CVD). ATP-citrate lyase (ACLY) is a key lipogenic enzyme that converts cytosolic citrate derived from tricarboxylic acid cycle (TCA cycle) to acetyl-CoA in the cytoplasm. Therefore, ACLY represents a link between mitochondria oxidative phosphorylation and cytosolic lipogenesis. In this study, we developed the small molecule with an enedioic acid structural moiety as a novel ACLY inhibitor, and its CoA-conjugated form -CoA inhibited ACLY activity with an IC = 5.31 ± 1.2 μmol/L . treatment reduced lipogenesis, and increased cholesterol efflux and . was rapidly absorbed after oral administration, exhibited a higher blood exposure than that of the approved ACLY inhibitor bempedoic acid (BA) used for hypercholesterolemia. Chronic treatment in hamsters and rhesus monkeys resulted in remarkable improvement of hyperlipidemia. Once daily oral administration of for 24 weeks prevented the occurrence of atherosclerosis in ApoE mice to a greater extent than that of BA treatment. Taken together, our data suggest that inhibition of ACLY by represents a promising strategy for the treatment of hypercholesterolemia.