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 Nε-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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