Discovery of Novel Tridentate Alkenyl Diacid Derivatives as Potent ATP Citrate Lyase Inhibitors for the Treatment of Hepatocellular Carcinoma

Metabolic reprogramming is a hallmark of hepatocellular carcinoma (HCC), with enhanced de novo lipogenesis playing a critical role in tumor progression. ATP citrate lyase (ACLY), linking carbohydrate metabolism to lipid biosynthesis, has emerged as a promising therapeutic target in HCC. Herein, we report the development of a series of novel tridentate alkenyl diacid derivatives as potent ACLY inhibitors. Guided by molecular docking and structure–activity relationship studies, we identified compound F28, which exhibited potent ACLY inhibitory activity (IC₅₀ = 0.87 ± 0.09 μM) and favorable pharmacokinetic properties. Compound F28 demonstrated antiproliferative activity in vitro across various cancer cell lines and attenuated lipogenesis in JHH7 and HepG2 cells. The administration of compound F28 reduced tumor burden and liver fibrosis in a high-fat diet combined with a chemotoxic agent-induced HCC mouse model. These results position compound F28 as a promising lead compound for the further development of ACLY inhibitors in HCC therapy.