Identification of Novel Disruptor of Telomeric Silencing 1-like (DOT1L) Inhibitors through Structure-Based Virtual Screening and Biological Assays

doi:10.1021/acs.jcim.5b00738

	Identification of Novel Disruptor of Telomeric Silencing 1-like (DOT1L) Inhibitors through Structure-Based Virtual Screening and Biological Assays
	Chen, Shijie 1,2; Li, Linjuan1,2 ; Chen, Yantao 2; Hu, Junchi 2; Liu, Jingqiu 2; Liu, Yu-Chih 3; Liu, Rongfeng 3; Zhang, Yuanyuan 2; Meng, Fanwang 2; Zhu, Kongkai 2; Lu, Junyan 2; Zheng, Mingyue 2; Chen, Kaixian1,2 ; Zhang, Jin 4; Jiang, Hualiang1,2 ; Yao, Zhiyi 5; Luo, Cheng 2
	2016-03
发表期刊	JOURNAL OF CHEMICAL INFORMATION AND MODELING (IF:5.6[JCR-2023],5.9[5-Year])
ISSN	1549-9596
卷号	56 期号:3 页码:527-534
发表状态	已发表
DOI	10.1021/acs.jcim.5b00738
摘要	Histone methyltransferases are involved in many important biological processes, and abnormalities in these enzymes are associated with tumorigenesis and progression. Disruptor of telomeric silencing 1-like (DOT1L), a key hub in histone lysine methyltransferases, has been reported to play an important role in the processes of mixed-lineage leukemia (MLL)-rearranged leukemias and validated to be a potential therapeutic target. In this study, we identified, a novel DOT1L inhibitor, DC_L115 (CAS no. 1163729-79-0), by combining structure-based virtual screening with biochemical analyses. This potent inhibitor DC_L115 shows high inhibitory activity toward DOT1L (IC50 = 1.5 mu M). Through a process of surface plasmon resonance-based binding assays, DC_L115 was founded to bind to DOT1L with a binding affinity of 0.6 mu M in vitro. Moreover, this compound selectively inhibits MLL-rearranged cell proliferation with an IC50 value of 37.1 mu M. We further predicted the binding modes of DC_L115 through molecular docking analysis and found that the inhibitor competitively occupies the binding site of S-adenosylmethionine. Overall, this study demonstrates the development of potent DOT1L inhibitors with novel scaffolds.
收录类别	SCI ; EI
语种	英语
资助项目	National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program"[2013ZX09507-004] ; National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program"[2013ZX09507001] ; National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program"[2014ZX09507002-005-012]
WOS研究方向	Pharmacology & Pharmacy ; Chemistry ; Computer Science
WOS类目	Chemistry, Medicinal ; Chemistry, Multidisciplinary ; Computer Science, Information Systems ; Computer Science, Interdisciplinary Applications
WOS记录号	WOS:000373247200008
出版者	AMER CHEMICAL SOC
EI入藏号	20161502223946
EI主题词	Amino acids ; Binding energy ; Binding sites ; Cell proliferation ; Diagnosis ; Surface plasmon resonance
EI分类号	Medicine and Pharmacology:461.6 ; Biology:461.9 ; Storage:694.4 ; Biochemistry:801.2 ; Physical Chemistry:801.4 ; Organic Compounds:804.1
WOS关键词	HISTONE METHYLTRANSFERASE DOT1L ; MLL-REARRANGED LEUKEMIA ; DRUG DISCOVERY ; SELECTIVE INHIBITORS ; H3K79 METHYLATION ; ACCURATE DOCKING ; FUSION PARTNERS ; SET DOMAIN ; POTENT ; GLIDE
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/1903
专题	生命科学与技术学院生命科学与技术学院_特聘教授组_陈凯先组免疫化学研究所_特聘教授组_蒋华良组生命科学与技术学院_博士生
通讯作者	Jiang, Hualiang; Yao, Zhiyi; Luo, Cheng
作者单位	1.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 200031, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, 555 Zu Chongzhi Rd, Shanghai 201203, Peoples R China 3.Shanghai ChemPartner LifeSci Co Ltd, Vitro Biol, 5 Bldg,998 Halei Rd, Shanghai 201203, Peoples R China 4.Shanghai Jiao Tong Univ, Renji Hosp, Sch Med, Dept Urol, Shanghai 200127, Peoples R China 5.Shanghai Inst Technol, Coll Chem & Environm Engn, Shanghai 210032, Peoples R China
第一作者单位	生命科学与技术学院
通讯作者单位	生命科学与技术学院
第一作者的第一单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Chen, Shijie,Li, Linjuan,Chen, Yantao,et al. Identification of Novel Disruptor of Telomeric Silencing 1-like (DOT1L) Inhibitors through Structure-Based Virtual Screening and Biological Assays[J]. JOURNAL OF CHEMICAL INFORMATION AND MODELING,2016,56(3):527-534.
APA	Chen, Shijie.,Li, Linjuan.,Chen, Yantao.,Hu, Junchi.,Liu, Jingqiu.,...&Luo, Cheng.(2016).Identification of Novel Disruptor of Telomeric Silencing 1-like (DOT1L) Inhibitors through Structure-Based Virtual Screening and Biological Assays.JOURNAL OF CHEMICAL INFORMATION AND MODELING,56(3),527-534.
MLA	Chen, Shijie,et al."Identification of Novel Disruptor of Telomeric Silencing 1-like (DOT1L) Inhibitors through Structure-Based Virtual Screening and Biological Assays".JOURNAL OF CHEMICAL INFORMATION AND MODELING 56.3(2016):527-534.