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 acti...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 IC50 value of 1.5μmol/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.展开更多
基金supported by grants fromthe"Personalized Medicines-Molecular Signature-based Drug Discovery and Development"Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12040328)the Medical Guidance Project of Shanghai ScienceandTechnology Commission(20S11903400)+1 种基金the Natural Science Foundation of Shanghai's 2021"Science and Technology InnovationAction Plan"(21ZR1475300)the National Natural Science Foundation of China(No.82170872).
文摘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 IC50 value of 1.5μmol/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.
