Development of Potent Type I Protein Arginine Methyltransferase (PRMT) Inhibitors of Leukemia Cell Proliferation
Wang, Chen1,2,3; Jiang, Hao2,3; Jin, Jia1; Xie, Yiqian2; Chen, Zhifeng4; Zhang, Hao2; Lian, Fulin2; Liu, Yu-Chih5; Zhang, Chenhua5; Ding, Hong2; Chen, Shijie2; Zhang, Naixia2; Zhang, Yuanyuan2; Jiang, Hualiang2; Chen, Kaixian2,4; Ye, Fei1; Yao, Zhiyi6; Luo, Cheng2
2017-11-09
Source PublicationJOURNAL OF MEDICINAL CHEMISTRY
ISSN0022-2623
Volume60Issue:21Pages:8888-8905
Status已发表
DOI10.1021/acs.jmedchem.7b01134
AbstractProtein 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.
Indexed BySCI ; IC
Language英语
Funding ProjectShanghai Sailing Program[17YF1423100]
WOS Research AreaPharmacology & Pharmacy
WOS SubjectChemistry, Medicinal
WOS IDWOS:000415140600016
PublisherAMER CHEMICAL SOC
WOS KeywordHISTONE DEACETYLASE INHIBITOR ; GENE-EXPRESSION ; DRUG DISCOVERY ; BIOLOGICAL EVALUATION ; SELECTIVE INHIBITORS ; METHYLATION ; CANCER ; ACTIVATION ; DOCKING ; VIVO
Original Document TypeArticle
Citation statistics
Cited Times:16[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://kms.shanghaitech.edu.cn/handle/2MSLDSTB/10017
Collection生命科学与技术学院
生命科学与技术学院_特聘教授组_陈凯先组
生命科学与技术学院_硕士生
Corresponding AuthorZhang, Yuanyuan; Ye, Fei; Yao, Zhiyi; Luo, Cheng
Affiliation1.Zhejiang Sci Tech Univ, Coll Life Sci, Hangzhou 310018, Zhejiang, Peoples R China
2.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
3.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China
4.ShanghaiTech Univ, Sch Life Sci & Technol, 100 Haike Rd, Shanghai 201210, Peoples R China
5.Shanghai ChemPartner Co Ltd, 5 Bldg,998,Halei Rd, Shanghai 201203, Peoples R China
6.Shanghai Inst Technol, Coll Chem & Environm Engn, Shanghai 210032, Peoples R China
Recommended Citation
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.
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