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

Hepatic cholesterol accumulation plays a significant role in hypercholesterolemia, leading to atherosclerosis and cardiovascular disease (CVD). ATP-citrate lyase (ACLY) is a crucial lipogenic enzyme that converts cytosolic citrate, sourced from the tricarboxylic acid (TCA) cycle, into acetyl-CoA in the cytoplasm. This makes ACLY a key link between mitochondrial oxidative phosphorylation and cytosolic de novo lipogenesis.

In this study, we developed 326E, a small molecule with an enedioic acid moiety, as a novel inhibitor of ACLY. Its CoA-conjugated form, 326E-CoA, inhibited ACLY activity with an IC50 of 5.31 ± 1.2 μmol/L in vitro. Treatment with 326E reduced de novo lipogenesis and increased cholesterol efflux both in vitro and in vivo. 326E was rapidly absorbed following oral administration and demonstrated higher blood exposure compared to the approved ACLY inhibitor bempedoic acid (BA), which is used for hypercholesterolemia. Chronic administration of 326E in hamsters and rhesus monkeys significantly improved hyperlipidemia. Furthermore, daily oral doses of 326E for 24 weeks prevented atherosclerosis in ApoE-/- mice more effectively than BA treatment. Overall, these findings suggest that ACLY inhibition by BMS303141 is a promising approach for treating hypercholesterolemia.