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Discovery of Novel Disruptor of Silencing Telomeric 1-Like (DOTI L) Inhibitors using a Target-Specific Scoring Function for the (S)-Adenosyl-L-methionine (SAM)-Dependent Methyltransferase Family

文献类型：期刊论文

作者Wang, Yulan2,3,4; Li, Linjuan1,2; Zhang, Bidong2,4; Xing, Jing2,4; Chen, Shijie2,4; Wan, Wei2,4; Song, Yakai2,5; Jiang, Hao2,4; Jiang, Hualiang1,2,4; Luo, Cheng2,4
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2017-03-09
卷号60期号:5页码:2026-2036
ISSN号0022-2623
DOI10.1021/acs.jmedchem.6b01785
文献子类Article
英文摘要The disruptor of telomeric silencing 1-like (DOT1L) protein is a histone H3K79 methyltransferase that plays a key role in transcriptional elongation and cell cycle regulation and is required for the development and maintenance of MLL-rearranged mixed lineage leukemia. Much effort has been dedicated toward discovering novel scaffold DOT1L inhibitors using different strategies. Here, we report the development and application of a target-specific scoring function, the SAM score, for (S)-adenosyl-Lmethionine (SAM)-dependent methyltransferases, for the discovery of novel DOT1L inhibitors. On the basis of the SAM score, we successfully identified a novel class of DOTIL inhibitors with a scaffold of [1,2,4]-triazolo-[3,4-b] [1,3,4]-thiadiazole, in which compound 6 exhibits an IC50 value of 8.3 mu M with selectivity versus other tested SAM -dependent methyltransferases. In cellular studies, 6 selectively targets DOT1L, blocks the proliferation of mixed lineage leukemia cell lines, and causes cell cycle arrest and apoptosis. Moreover, we analyzed the putative binding modes of 6 and its analogues obtained by molecular docking, which may assist with the future development of DOT1L inhibitors with improved potency and selectivity profiles.
WOS关键词MIXED-LINEAGE LEUKEMIA ; HISTONE METHYLTRANSFERASE ; LIGAND INTERACTIONS ; H3K79 METHYLATION ; DRUG DISCOVERY ; LIBRARIES ; DOCKING ; SET
资助项目Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12050201] ; National Basic Research Program[2015CB910304] ; National Natural Science Foundation of China[21210003] ; National Natural Science Foundation of China[81230076] ; National Natural Science Foundation of China[81430084] ; National Key Research & Development Plan[2016YF1201003] ; Fund of State Key Laboratory of Toxicology and Medical Countermeasures, Academy of Military Medical Science[TMC201505] ; State Key Laboratory of Natural and Biomimetic Drugs[00000000]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000396296100028
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/272744]  
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Luo, Cheng; Zheng, Mingyue
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, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China;
3.Peking Univ, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China;
4.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China;
5.Univ Sci & Technol China, Nano Sci & Technol Inst, Suzhou 215123, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Yulan,Li, Linjuan,Zhang, Bidong,et al. Discovery of Novel Disruptor of Silencing Telomeric 1-Like (DOTI L) Inhibitors using a Target-Specific Scoring Function for the (S)-Adenosyl-L-methionine (SAM)-Dependent Methyltransferase Family[J]. JOURNAL OF MEDICINAL CHEMISTRY,2017,60(5):2026-2036.
APA Wang, Yulan.,Li, Linjuan.,Zhang, Bidong.,Xing, Jing.,Chen, Shijie.,...&Zheng, Mingyue.(2017).Discovery of Novel Disruptor of Silencing Telomeric 1-Like (DOTI L) Inhibitors using a Target-Specific Scoring Function for the (S)-Adenosyl-L-methionine (SAM)-Dependent Methyltransferase Family.JOURNAL OF MEDICINAL CHEMISTRY,60(5),2026-2036.
MLA Wang, Yulan,et al."Discovery of Novel Disruptor of Silencing Telomeric 1-Like (DOTI L) Inhibitors using a Target-Specific Scoring Function for the (S)-Adenosyl-L-methionine (SAM)-Dependent Methyltransferase Family".JOURNAL OF MEDICINAL CHEMISTRY 60.5(2017):2026-2036.

入库方式： OAI收割

来源：上海药物研究所

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