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

doi:10.1016/j.bmc.2018.02.020

	Discovery of potent DOT1L inhibitors by AlphaLISA based High Throughput Screening assay
	Song, Yakai 1,2; Li, Linjuan2,3,4 ; Chen, Yantao 2,3; Liu, Jingqiu 2,5; Xiao, Senhao2,3,4 ; Lian, Fulin 2; Zhang, Naixia 2; Ding, Hong 2,5; Zhang, Yuanyuan 2,5; Chen, Kaixian 2,6; Jiang, Hualiang 2,5,6; Zhang, Chenhua 6; Liu, Yu-Chih 6; Chen, Shijie 2,5; Luo, Cheng 2,5
	2018-05
发表期刊	BIOORGANIC & MEDICINAL CHEMISTRY (IF:3.3[JCR-2023],3.1[5-Year])
ISSN	0968-0896
卷号	26 期号:8 页码:1751-1758
发表状态	已发表
DOI	10.1016/j.bmc.2018.02.020
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.
关键词	DOT1L MLL-rearranged leukemia AlphaLISA HTS Novel inhibitors
收录类别	SCI ; SCIE ; IC
语种	英语
资助项目	Shanghai Sailing Program[17YF1423100]
WOS研究方向	Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
WOS类目	Biochemistry & Molecular Biology ; Chemistry, Medicinal ; Chemistry, Organic
WOS记录号	WOS:000429533300035
出版者	PERGAMON-ELSEVIER SCIENCE LTD
WOS关键词	HISTONE METHYLTRANSFERASE DOT1L ; MIXED-LINEAGE LEUKEMIA ; H3K79 METHYLATION ; ACCURATE DOCKING ; DRUG DISCOVERY ; GLIDE ; IDENTIFICATION ; DISRUPTOR ; DYNAMICS ; FAMILY
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/20215
专题	生命科学与技术学院生命科学与技术学院_硕士生生命科学与技术学院_博士生
通讯作者	Chen, Shijie; Luo, Cheng
作者单位	1.Univ Sci & Technol China, Nano Sci & Technol Inst, Suzhou 215123, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, 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.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 6.Shanghai ChemPartner Co Ltd, 5 Bldg,998 Halei 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.