Discovery of potent DOT1L inhibitors by AlphaLISA based High Throughput Screening assay

doi:10.1016/j.bmc.2018.02.020

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	Discovery of potent DOT1L inhibitors by AlphaLISA based High Throughput Screening assay
	Song, Yakai 2,3; Li, Linjuan 3,4,5; Chen, Yantao 3,4; Liu, Jingqiu 3,6; Xiao, Senhao 3,4,5; Lian, Fulin 3; Zhang, Naixia3 ; Ding, Hong3,6 ; Zhang, Yuanyuan 3,6; Chen, Kaixian1,3
刊名	BIOORGANIC & MEDICINAL CHEMISTRY
	2018-05-01
卷号	26 期号:8 页码:1751-1758
关键词	DOT1L MLL-rearranged leukemia AlphaLISA HTS Novel inhibitors
ISSN号	0968-0896
DOI	10.1016/j.bmc.2018.02.020
文献子类	Article
英文摘要	DOT1L (the disruptor of telomeric silencing 1-like), through its methyltransferase activity of H3K79, plays essential roles in transcriptional regulation, cell cycle regulation, and DNA damage response. In addition, DOT1L is believed to be involved in the development of MLL-rearranged leukemia driven by the MLL (mixed-lineage leukemia) fusion proteins, which thus to be a crucial target for leukemia therapy. Hence, discovering of novel DOT1L inhibitors has been in a great demand. In this study, we initiated the discovering process from setting up the AlphaLISA based High Throughput Screening (HTS) assay of DOT1L. Combining with radioactive inhibition assay and Surface Plasmon Resonance (SPR) binding assay, we identified compound 3 and its active analogues as novel DOT1L inhibitors with IC50 values range from 7 mu M to 20 mu M in vitro. Together with the analysis of structure activity relationships (SAR) and binding modes of these compounds, we provided clues to assist in the future development of more potent DOT1L inhibitors. Moreover, compounds 3 and 9 effectively inhibited the proliferation of MLL-rearranged leukemia cells MV4-11, which could induce cell cycle arrest and apoptosis. In conclusion, we developed a HTS platform based on AlphaLISA method for screening and discovery of DOT1L novel inhibitor, through which we discovered compound 3 and its analogues as potent DOT1L inhibitors with promising MLL-rearranged leukemia therapeutic application. (C) 2018 Elsevier Ltd. All rights reserved.
资助项目	Ministry of Science and Technology of China (National Key R&D Program of China)[2017YFB0202600] ; Ministry of Science and Technology of China (National Key R&D Program 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[81703415] ; Shanghai Sailing Program[17YF1423100]
WOS关键词	HISTONE METHYLTRANSFERASE DOT1L ; MIXED-LINEAGE LEUKEMIA ; H3K79 METHYLATION ; ACCURATE DOCKING ; DRUG DISCOVERY ; GLIDE ; IDENTIFICATION ; DISRUPTOR ; DYNAMICS ; FAMILY
WOS研究方向	Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
语种	英语
出版者	PERGAMON-ELSEVIER SCIENCE LTD
WOS记录号	WOS:000429533300035
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279784]
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	Chen, Shijie; Luo, Cheng
作者单位	1.Shanghai ChemPartner Co Ltd, 5 Bldg,998 Halei Rd, Shanghai 201203, Peoples R China 2.Univ Sci & Technol China, Nano Sci & Technol Inst, Suzhou 215123, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, 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.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Song, Yakai,Li, Linjuan,Chen, Yantao,et al. Discovery of potent DOT1L inhibitors by AlphaLISA based High Throughput Screening assay[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2018,26(8):1751-1758.
APA	Song, Yakai.,Li, Linjuan.,Chen, Yantao.,Liu, Jingqiu.,Xiao, Senhao.,...&Luo, Cheng.(2018).Discovery of potent DOT1L inhibitors by AlphaLISA based High Throughput Screening assay.BIOORGANIC & MEDICINAL CHEMISTRY,26(8),1751-1758.
MLA	Song, Yakai,et al."Discovery of potent DOT1L inhibitors by AlphaLISA based High Throughput Screening assay".BIOORGANIC & MEDICINAL CHEMISTRY 26.8(2018):1751-1758.