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Development of Potent Type I Protein Arginine Methyltransferase (PRMT) Inhibitors of Leukemia Cell Proliferation

文献类型：期刊论文

作者Wang, Chen2,3,4; Jiang, Hao3,4; Jin, Jia2; Xie, Yiqian3; Chen, Zhifeng5; Zhang, Hao3; Lian, Fulin3; Liu, Yu-Chih1; Zhang, Chenhua1; Ding, Hong3
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2017-11-09
卷号60期号:21页码:8888-8905
ISSN号0022-2623
DOI10.1021/acs.jmedchem.7b01134
文献子类Article
英文摘要Protein Arginine Methyltransferases (PRMTs) are crucial players in diverse biological processes, and dysregulation of PRMTs has been linked to various human diseases, especially cancer. Therefore, small molecules targeting PRMTs have profound impact for both academic functional studies and clinical disease treatment. Here, we report the discovery of N-1-(2-((2-chlorophenyl)thio)benzyl)-N-1-methylethane-1,2-diamine (28d, DCPR049_12), a highly potent inhibitor of type I PRMTs that has good selectivity against a panel of other methyltransferases. Compound 28d effectively inhibits cell proliferation in several leukemia cell lines and reduces the cellular asymmetric arginine dirnethylation levels. Serving as an effective inhibitor, 28d demonstrates the mechanism of cell killing in both cell cycle arrest and apoptotic effect as well as downregulation of the pivotal mixed lineage leukemia (MLL) fusion target genes such as HOXA9 and MEIS1, which reflects the critical roles of type I PRMTs in MLL leukemia. These studies present 28d as a valuable inhibitor to investigate the role of type I PRMTs in cancer and other diseases.
WOS关键词HISTONE DEACETYLASE INHIBITOR ; GENE-EXPRESSION ; DRUG DISCOVERY ; BIOLOGICAL EVALUATION ; SELECTIVE INHIBITORS ; METHYLATION ; CANCER ; ACTIVATION ; DOCKING ; VIVO
资助项目Ministry of Science and Technology of China[2015CB910304] ; National Natural Science Foundation of China[21472208] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[81430084] ; National Natural Science Foundation of China[21210003] ; National Natural Science Foundation of China[81230076] ; National Natural Science Foundation of China[81402849] ; Public Projects of Zhejiang Province[2015C33159] ; Public Projects of Zhejiang Province[2016C31017] ; Zhejiang Province Natural Science Foundation[LY18H300008] ; Science Foundation of Zhejiang Sci-Tech University[13042163-Y] ; Science Foundation of Zhejiang Sci-Tech University[13042159-Y] ; Zhejiang Provincial Top Key Discipline of Biology, China Postdoctoral Science Foundation[2016M590391] ; Zhejiang Provincial Top Key Discipline of Biology, China Postdoctoral Science Foundation[2016M601676] ; National Key R&D Program of China[2017YFB0202600] ; Shanghai Sailing Program[17YF1423100]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000415140600016
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/272408]  
专题药物发现与设计中心
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
通讯作者Zhang, Yuanyuan; Ye, Fei; Yao, Zhiyi; Luo, Cheng
作者单位1.Shanghai ChemPartner Co Ltd, 5 Bldg,998,Halei Rd, Shanghai 201203, Peoples R China;
2.Zhejiang Sci Tech Univ, Coll Life Sci, Hangzhou 310018, Zhejiang, Peoples R China;
3.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, State Key Lab Drug Res,Drug Discovery & Design Ct, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China;
4.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China;
5.ShanghaiTech Univ, Sch Life Sci & Technol, 100 Haike Rd, Shanghai 201210, Peoples R China;
6.Shanghai Inst Technol, Coll Chem & Environm Engn, Shanghai 210032, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Chen,Jiang, Hao,Jin, Jia,et al. Development of Potent Type I Protein Arginine Methyltransferase (PRMT) Inhibitors of Leukemia Cell Proliferation[J]. JOURNAL OF MEDICINAL CHEMISTRY,2017,60(21):8888-8905.
APA Wang, Chen.,Jiang, Hao.,Jin, Jia.,Xie, Yiqian.,Chen, Zhifeng.,...&Luo, Cheng.(2017).Development of Potent Type I Protein Arginine Methyltransferase (PRMT) Inhibitors of Leukemia Cell Proliferation.JOURNAL OF MEDICINAL CHEMISTRY,60(21),8888-8905.
MLA Wang, Chen,et al."Development of Potent Type I Protein Arginine Methyltransferase (PRMT) Inhibitors of Leukemia Cell Proliferation".JOURNAL OF MEDICINAL CHEMISTRY 60.21(2017):8888-8905.

入库方式： OAI收割

来源：上海药物研究所

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