Discovery of Novel Long‐Chain Alkenyl Diacid Derivatives as ACLY Inhibitors

Comprehensive Summary ATP citrate lyase (ACLY) synthesizes cytosolic acetyl coenzyme A (acetyl‐CoA), an essential biosynthetic precursor for lipid synthesis and the acetyl donor required for protein acetylation. The aberrant expression and activity of ACLY has been documented in multiple human cancers. ETC‐1002 is an indirect ACLY inhibitor, and it has recently been approved by the FDA as an additional therapeutic option in high‐risk hypercholesterolemia patients unable to meet goals with standard therapy. In this work, we identified a series of novel long‐chain alkenyl diacids as potent direct ACLY inhibitors, and comprehensive structure‐activity relationship analysis showed that compound 18f was the most potent ACLY inhibitor with an IC 50 value of 1.5 μmol/L. Subsequent ester formation of 18f gave a new series of compounds such as 25f that maintained ACLY inhibitory activity and improved antitumor cell proliferation effects.