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

doi:10.1021/acs.jmedchem.6b01785

	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
	Wang, Yulan 1,2,3; Li, Linjuan1,4 ; Zhang, Bidong 1,3; Xing, Jing 1,3; Chen, Shijie 1,3; Wan, Wei 1,3; Song, Yakai 1,5; Jiang, Hao 1,3; Jiang, Hualiang1,3,4 ; Luo, Cheng 1,3; Zheng, Mingyue 1,3
	2017-03-09
发表期刊	JOURNAL OF MEDICINAL CHEMISTRY (IF:6.8[JCR-2023],7.1[5-Year])
ISSN	0022-2623
卷号	60 期号:5 页码:2026-2036
发表状态	已发表
DOI	10.1021/acs.jmedchem.6b01785
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.
收录类别	SCI
语种	英语
资助项目	Fund of State Key Laboratory of Toxicology and Medical Countermeasures, Academy of Military Medical Science[TMC201505]
WOS研究方向	Pharmacology & Pharmacy
WOS类目	Chemistry, Medicinal
WOS记录号	WOS:000396296100028
出版者	AMER CHEMICAL SOC
WOS关键词	HISTONE ; METHYLATION ; LEUKEMIA
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/1477
专题	生命科学与技术学院免疫化学研究所_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	Luo, Cheng; Zheng, Mingyue
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 2.Peking Univ, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China 3.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 4.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 200031, 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.