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

文献类型：期刊论文

作者Chen, Shijie2,3; Li, Linjuan2,3; Chen, Yantao3; Hu, Junchi3; Liu, Jingqiu3; Liu, Yu-Chih4; Liu, Rongfeng4; Zhang, Yuanyuan3; Meng, Fanwang3; Zhu, Kongkai3
刊名JOURNAL OF CHEMICAL INFORMATION AND MODELING
出版日期2016-03
卷号56期号:3页码:527-534
ISSN号1549-9596
DOI10.1021/acs.jcim.5b00738
文献子类Article
英文摘要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.
WOS关键词HISTONE METHYLTRANSFERASE DOT1L ; MLL-REARRANGED LEUKEMIA ; DRUG DISCOVERY ; SELECTIVE INHIBITORS ; H3K79 METHYLATION ; ACCURATE DOCKING ; FUSION PARTNERS ; SET DOMAIN ; POTENT ; GLIDE
资助项目National Basic Research Program[2015CB910304] ; Hi-Tech Research and Development Program of China[2014AA01A302] ; National Natural Science Foundation of China[21210003] ; National Natural Science Foundation of China[81230076] ; National Natural Science Foundation of China[81430084] ; National Natural Science Foundation of China[81202398] ; National Natural Science Foundation of China[91229204] ; 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
语种英语
WOS记录号WOS:000373247200008
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/276117]  
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Jiang, Hualiang; Yao, Zhiyi; Luo, Cheng
作者单位1.Shanghai Jiao Tong Univ, Renji Hosp, Sch Med, Dept Urol, Shanghai 200127, Peoples R China;
2.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 200031, Peoples R China;
3.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;
4.Shanghai ChemPartner LifeSci Co Ltd, Vitro Biol, 5 Bldg,998 Halei Rd, Shanghai 201203, Peoples R China;
5.Shanghai Inst Technol, Coll Chem & Environm Engn, Shanghai 210032, Peoples R China
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.

入库方式： OAI收割

来源：上海药物研究所

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