The regulatory mechanisms and inhibitors of isocitrate dehydrogenase 1 in cancer  

作　　者：Yang Liu Wei Xu Mingxue Li Yueying Yang Dejuan Sun Lidian Chen Hua Li Lixia Chen 

机构地区：[1]Wuya College of Innovation,Key Laboratory of Structure-Based Drug Design&Discovery,Ministry of Education,Shenyang Pharmaceutical University,Shenyang 110016,China [2]The Institute of Rehabilitation Industry,Fujian University of Traditional Chinese Medicine,Fuzhou 350122,China [3]Institute of Structural Pharmacology&TCM Chemical Biology,College of Pharmacy,Fujian University of Traditional Chinese Medicine,Fuzhou 350122,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第4期1438-1466,共29页药学学报（英文版）

基　　金：supported by National Natural Science Foundation of China(NSFC)(No.81773637,82141216,U1803122);Chunhui Program-Cooperative Research Project of the Ministry of Education;Shenyang Young and Middle-aged Innovative Talents Support Program(RC210446,China);Liaoning Province Natural Science Foundation(Nos.2022-MS-241,2020-MZLH-31,China);support from National-Local Joint Engineering Research Center for Molecular Biotechnology of Fujian&Taiwan TCM,Fujian Key Laboratory of Chinese Materia Medica,Fujian University Key Laboratory for Research and Development of TCM Resources,at Fujian University of Traditional Chinese Medicine。

摘　　要：Reprogramming of energy metabolism is one of the basic characteristics of cancer and has been proved to be an important cancer treatment strategy.Isocitrate dehydrogenases(IDHs)are a class of key proteins in energy metabolism,including IDH1,IDH2,and IDH3,which are involved in the oxidative decarboxylation of isocitrate to yield a-ketoglutarate(a-KG).Mutants of IDH1 or IDH2 can produce D-2-hydroxyglutarate(D-2HG)with a-KG as the substrate,and then mediate the occurrence and development of cancer.At present,no IDH3 mutation has been reported.The results of pan-cancer research showed that IDH1 has a higher mutation frequency and involves more cancer types than IDH2,implying IDH1 as a promising anti-cancer target.Therefore,in this review,we summarized the regulatory mechanisms of IDH1 on cancer from four aspects:metabolic reprogramming,epigenetics,immune microenvironment,and phenotypic changes,which will provide guidance for the understanding of IDH1 and exploring leading-edge targeted treatment strategies.In addition,we also reviewed available IDH1 inhibitors so far.The detailed clinical trial results and diverse structures of preclinical candidates illustrated here will provide a deep insight into the research for the treatment of IDH1-related cancers.

关 键 词：IDH1 CANCER Regulatory mechanisms IDH1 inhibitors D-2HG Metabolic reprogramming EPIGENETICS Immune microenvironment 

分 类 号：R914[医药卫生—药物化学]