Identification of a cellularly active SIRT6 allosteric activator

Nat Chem Biol. 2018 Dec;14(12):1118-1126. doi: 10.1038/s41589-018-0150-0.

Zhimin Huang ^# ¹, Junxing Zhao ^# ¹, Wei Deng ^# ², Yingyi Chen ^# ¹, Jialin Shang ^# ¹, Kun Song ¹, Lu Zhang ¹, Chengxiang Wang ¹, Shaoyong Lu ¹, Xiuyan Yang ¹, Bin He ³, Jinrong Min ⁴, Hao Hu ⁵, Minjia Tan ⁵, Jianrong Xu ¹, Qiufen Zhang ¹, Jie Zhong ¹, Xiaoxiang Sun ⁶, Zhiyong Mao ⁶, Houwen Lin ⁷, Mingzhe Xiao ², Y Eugene Chin ², Hualiang Jiang ⁵, Ying Xu ⁸, Guoqiang Chen ⁹, Jian Zhang ¹⁰ ¹¹ ¹²

Affiliations

1 Key Laboratory of Cell Differentiation and Apoptosis, Ministry of Education, Department of Pathophysiology, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
2 Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
3 Engineering Research Center for the Development and Application of Ethnic Medicine and TCM, Ministry of Education, Guizhou Medical University, Guiyang, China.
4 Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
5 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
6 School of Life Sciences and Technology, Tongji University, Shanghai, China.
7 Basic Clinical Research Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
8 Key Laboratory of Cell Differentiation and Apoptosis, Ministry of Education, Department of Pathophysiology, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China. [email protected].
9 Key Laboratory of Cell Differentiation and Apoptosis, Ministry of Education, Department of Pathophysiology, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China. [email protected].
10 Key Laboratory of Cell Differentiation and Apoptosis, Ministry of Education, Department of Pathophysiology, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China. [email protected].
11 Basic Clinical Research Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
12 Medicinal Bioinformatics Center, Shanghai JiaoTong University School of Medicine, Shanghai, China. [email protected].
# Contributed equally.

PMID: 30374165 DOI: 10.1038/s41589-018-0150-0

Abstract

SIRT6, a member of the SIRT deacetylase family, is responsible for deacetylation of histone H3 N^ε-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.

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