Development of high potent and selective Bcl-2 inhibitors bearing the structural elements of natural product artemisinin

doi:10.1016/j.ejmech.2018.09.059

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	Development of high potent and selective Bcl-2 inhibitors bearing the structural elements of natural product artemisinin
	Liu, Xiaohua 3; Zhang, Yu 2; Huang, Wenjing 2; Luo, Jia 2; Li, Yang3 ; Tan, Wenfu 2; Zhang, Ao1,3,4
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2018-11-05
卷号	159 页码:149-165
关键词	Apoptosis Artemisinin Bcl-2 Venetoclax Selectivity
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2018.09.059
文献子类	Article
英文摘要	By taking advantage of the apoptosis-inducing capacity of artemisinin derivatives, we developed several series of compounds by merging the basic structural elements of the natural product artemisinin into the P2 interaction pocket of the clinically prescribed Bcl-2 inhibitor venetoclax. Most of the new compounds displayed improved biochemical potency against Bcl-2 and high selectivity over Bcl-xL. Specifically, compounds 27c and 34c were found to be the most potent with IC50 values less than 2.0 nM. Unfortunately, these compounds only showed moderate antiproliferative effects against Bcl-2 dependent cells. Though further structural optimization is needed to improve the cellular absorptive permeability, the current approach represents an alternative strategy to develop novel Bcl-2 inhibitors with greater selectivity over Bcl-xL, which is related to the off-target adverse effects of venetoclax. (C) 2018 Elsevier Masson SAS. All rights reserved.
资助项目	National Science Foundation of China[81773565] ; National Science Foundation of China[81773767] ; National Science Foundation of China[81430080] ; National Science Foundation of China[81573452] ; National Program on Key Basic Research Project of China[2015CB910603-004] ; International Cooperative Program of the Chinese Academy of Sciences[GJHZ1622] ; Key Program of the Frontier Science of the Chinese Academy of Sciences[160621] ; Shanghai Commission of Science and Technology[16XD1404600] ; Shanghai Commission of Science and Technology[14431900400] ; Shanghai Commission of Science and Technology[16140902500]
WOS关键词	ACUTE LYMPHOBLASTIC-LEUKEMIA ; PHARMACOLOGICAL EVALUATION ; ANTICANCER AGENTS ; CANCER-CELLS ; DERIVATIVES ; APOPTOSIS ; DISCOVERY ; PROTEINS ; DIMERS ; DIHYDROARTEMISININ
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:000449237100012
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279498]
专题	药理学第一研究室中科院受体结构与功能重点实验室新药研究国家重点实验室药物化学研究室
通讯作者	Tan, Wenfu; Zhang, Ao
作者单位	1.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China; 2.Fudan Univ, Sch Pharm, Dept Pharmacol, Shanghai 201203, Peoples R China; 3.Chinese Acad Sci, SIMM, State Key Lab Drug Res, Key Lab Receptor Res, Shanghai 201203, Peoples R China; 4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式 GB/T 7714	Liu, Xiaohua,Zhang, Yu,Huang, Wenjing,et al. Development of high potent and selective Bcl-2 inhibitors bearing the structural elements of natural product artemisinin[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2018,159:149-165.
APA	Liu, Xiaohua.,Zhang, Yu.,Huang, Wenjing.,Luo, Jia.,Li, Yang.,...&Zhang, Ao.(2018).Development of high potent and selective Bcl-2 inhibitors bearing the structural elements of natural product artemisinin.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,159,149-165.
MLA	Liu, Xiaohua,et al."Development of high potent and selective Bcl-2 inhibitors bearing the structural elements of natural product artemisinin".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 159(2018):149-165.