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Identification of a cellularly active SIRT6 allosteric activator

文献类型：期刊论文

作者Huang, Zhimin5; Zhao, Junxing5; Deng, Wei4; Chen, Yingyi5; Shang, Jialin5; Song, Kun5; Zhang, Lu5; Wang, Chengxiang5; Lu, Shaoyong5; Yang, Xiuyan5
刊名NATURE CHEMICAL BIOLOGY
出版日期2018-12
卷号14期号:12页码:1118-+
ISSN号1552-4450
DOI10.1038/s41589-018-0150-0
文献子类Article
英文摘要SIRT6, a member of the SIRT deacetylase family, is responsible for deacetylation of histone H3 N-epsilon-acetyl-lysines 9 (H3K9ac) and 56 (H3K56ac). As a tumor suppressor, SIRT6 has frequently been found to have low expression in various cancers. Here, we report the identification of MDL-800, a selective SIRT6 activator. MDL-800 increased the deacetylase activity of SIRT6 by up to 22-fold via binding to an allosteric site; this interaction led to a global decrease in H3K9ac and H3K56ac levels in human hepatocellular carcinoma (HCC) cells. Consequently, MDL-800 inhibited the proliferation of HCC cells via SIRT6-driven cell-cycle arrest and was effective in a tumor xenograft model. Together, these data demonstrate that pharmacological activation of SIRT6 is a potential therapeutic approach for the treatment of HCC. MDL-800 is a first-in-class small-molecule cellular SIRT6 activator that can be used to physiologically and pathologically investigate the roles of SIRT6 deacetylation.
WOS关键词CYCLIN-DEPENDENT KINASES ; DEACETYLASE ACTIVITY ; POTENTIAL MEDIATOR ; SMALL MOLECULES ; ADP-RIBOSE ; DNA-REPAIR ; CANCER ; INHIBITOR ; HISTONE ; LYSINE
资助项目National Basic Research Program of China (973 Program)[2015CB910403] ; National Natural Science Foundation of China[81721004] ; National Natural Science Foundation of China[91753117] ; National Natural Science Foundation of China[81322046] ; National Natural Science Foundation of China[81302698] ; National Natural Science Foundation of China[31671459] ; National Natural Science Foundation of China[U1605221] ; National Natural Science Foundation of China[2181001006] ; Program for Changjiang Scholars[00000000] ; Innovative Research Team of the University of the Ministry Education of China[00000000] ; CAS Interdisciplinary Innovation Team[00000000] ; Innovation Program of the Shanghai Municipal Education Commission[00000000] ; State Key Laboratory of Luminescence and application[SKLA-2016-12] ; Strategic Priority Research Program of the Chinese Academy of Sciences, 'Personalized Medicines-Molecular Signature-based Drug Discovery and Development'[XDA12040100]
WOS研究方向Biochemistry & Molecular Biology
语种英语
出版者NATURE PUBLISHING GROUP
WOS记录号WOS:000450230300013
源URL[http://119.78.100.183/handle/2S10ELR8/279484]  
专题化学蛋白质组学研究中心
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
药物发现与设计中心
通讯作者Xu, Ying; Chen, Guoqiang; Zhang, Jian
作者单位1.Shanghai Jiao Tong Univ, Basic Clin Res Ctr, Renji Hosp, Sch Med, Shanghai, Peoples R China;
2.Shanghai Jiao Tong Univ, Med Bioinformat Ctr, Sch Med, Shanghai, Peoples R China
3.Guizhou Med Univ, Engn Res Ctr Dev & Applicat Ethn Med & TCM, Minist Educ, Guiyang, Guizhou, Peoples R China;
4.Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai, Peoples R China;
5.Shanghai Jiao Tong Univ, Key Lab Cell Differentiat & Apoptosis, Minist Educ, Dept Pathophysiol,Ruijin Hosp, Shanghai, Peoples R China;
6.Univ Toronto, Struct Genom Consortium, Toronto, ON, Canada;
7.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai, Peoples R China;
8.Tongji Univ, Sch Life Sci & Technol, Shanghai, Peoples R China;
推荐引用方式
GB/T 7714		 Huang, Zhimin,Zhao, Junxing,Deng, Wei,et al. Identification of a cellularly active SIRT6 allosteric activator[J]. NATURE CHEMICAL BIOLOGY,2018,14(12):1118-+.
APA Huang, Zhimin.,Zhao, Junxing.,Deng, Wei.,Chen, Yingyi.,Shang, Jialin.,...&Zhang, Jian.(2018).Identification of a cellularly active SIRT6 allosteric activator.NATURE CHEMICAL BIOLOGY,14(12),1118-+.
MLA Huang, Zhimin,et al."Identification of a cellularly active SIRT6 allosteric activator".NATURE CHEMICAL BIOLOGY 14.12(2018):1118-+.

入库方式： OAI收割

来源：上海药物研究所

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