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

作　　者：Gao-Lei Song Lei Cao Mei Zhang Yu-Rou Yang Jie Ma Zhi-Fu Xie Jing-Ya Li Fa-Jun Nan 

机构地区：[1]State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China [2]University of Chinese Academy of Sciences,No.19A Yuquan Road,Beijing 100049,China [3]Yantai Key Laboratory of Nanomedicine&Advanced Preparations,Yantai Institute of Materia Medica,Yantai,Shandong 264000,China

出　　处：《Chinese Journal of Chemistry》2022年第22期2663-2670,共8页中国化学（英文版）

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);the Natural Science Foundation of Shanghai's 2021"Science and Technology InnovationAction Plan"(21ZR1475300);the National Natural Science Foundation of China(No.82170872).

摘　　要：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.

关 键 词：Alkenyl diacid derivatives Cancer ACLY inhibitors ACETYL-COA Structure-activity relationships 

分 类 号：O62[理学—有机化学]