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Structure-based design, synthesis and bioactivity evaluation of macrocyclic inhibitors of mutant isocitrate dehydrogenase 2 (IDH2) displaying activity in acute myeloid leukemia cells

文献类型：期刊论文

作者Che, Jinxin1; Huang, Feng1; Zhang, Mengmeng2; Xu, Gaoya2; Qu, Bingxue1; Gao, Jian1; Chen, Binhui1; Zhang, Jianjun3; Ying, Huazhou1; Hu, Yongzhou1
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2020-10-01
卷号203页码:19
ISSN号0223-5234
关键词Metabolic pathways Isocitrate dehydrogenase 2 Conformational restriction Macrocyclic derivatives Inhibitors
DOI10.1016/j.ejmech.2020.112491
通讯作者Gao, Anhui(ahgao@simm.ac.cn) ; Li, Jia(jli@simm.ac.cn) ; Dong, Xiaowu(dongxw@zju.edu.cn)
英文摘要The enzymes involved in the metabolic pathways in cancer cells have been demonstrated as important therapeutic targets such as the isocitrate dehydrogenase 2 (IDH2). A series of macrocyclic derivatives was designed based on the marketed IDH2 inhibitor AG-221 by using the conformational restriction strategy. The resulted compounds showed moderate to good inhibitory potential against different IDH2-mutant enzymes. Amongst, compound C6 exhibited better IDH2(R140Q) inhibitory potency than AG 221, and showed excellent activity of 2-hydroxyglutarate (2-HG) suppression in vitro and its mesylate displayed good pharmacokinetic profiles. Moreover, C6 performed strong binding mode to IDH2(R140Q) after computational docking and dynamic simulation, which may serve as a good starting point for further development. (C) 2020 Elsevier Masson SAS. All rights reserved.
WOS关键词BIOLOGICAL EVALUATION ; CANCER ; MUTATIONS ; DERIVATIVES
资助项目National Natural Science Foundation of China ; China Post-doctoral Science Foundation ; Zhejiang Provincial Natural Science Foundation of China ; Zhejiang Chinese Medicinal University Foundation ; National Major Scientific and Technological Special Project for Significant New Drugs Development ; Science and Technology Commission of Shanghai Municipality
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号WOS:000568867400001
源URL[http://119.78.100.183/handle/2S10ELR8/291157]  
专题新药研究国家重点实验室
通讯作者Gao, Anhui; Li, Jia; Dong, Xiaowu
作者单位1.Zhejiang Univ, Coll Pharmaceut Sci, Hangzhou Inst Innovat Med, ZJU ENS Joint Lab Med Chem,Zhejiang Prov Key Lab, Hangzhou 310058, Peoples R China
2.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Zhejiang Chinese Med Univ, Zhejiang Prov Hosp Tradit Chinese Med, Dept Pharm, Affiliated Hosp 1, Hangzhou 310058, Peoples R China
4.Pilot Natl Lab Marine Sci & Technol Qingdao, Open Studio Druggabil Res Marine Nat Prod, 1 Wenhai Rd, Qingdao 266237, Peoples R China
推荐引用方式
GB/T 7714		 Che, Jinxin,Huang, Feng,Zhang, Mengmeng,et al. Structure-based design, synthesis and bioactivity evaluation of macrocyclic inhibitors of mutant isocitrate dehydrogenase 2 (IDH2) displaying activity in acute myeloid leukemia cells[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2020,203:19.
APA Che, Jinxin.,Huang, Feng.,Zhang, Mengmeng.,Xu, Gaoya.,Qu, Bingxue.,...&Dong, Xiaowu.(2020).Structure-based design, synthesis and bioactivity evaluation of macrocyclic inhibitors of mutant isocitrate dehydrogenase 2 (IDH2) displaying activity in acute myeloid leukemia cells.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,203,19.
MLA Che, Jinxin,et al."Structure-based design, synthesis and bioactivity evaluation of macrocyclic inhibitors of mutant isocitrate dehydrogenase 2 (IDH2) displaying activity in acute myeloid leukemia cells".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 203(2020):19.

入库方式： OAI收割

来源：上海药物研究所

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