Tier 3 — preclinical

Identification of a cellularly active SIRT6 allosteric activator

Zhimin Huang, Junxing Zhao, Wei Deng, Yingyi Chen, Jialin Shang, Kun Song, Lu Zhang, Chengxiang Wang, Shaoyong Lu, Xiuyan Yang, Bin He, Jinrong Min, Hao Hu, Minjia Tan, Jianrong Xu, Qiufen Zhang, Jie Zhong, Xiaoxiang Sun, Zhiyong Mao, Houwen Lin, Mingzhe Xiao, Y Eugene Chin, Hualiang Jiang, Ying Xu, Guoqiang Chen, Jian Zhang
Nature Chemical Biology 2018 14(12):1118-1126

Bibliography

PubMed
PMID 30374165
DOI
10.1038/s41589-018-0150-0
Funding
Supported by the National Basic Research Program of China (2015CB910403), National Natural Science Foundation of China grants including 81721004, 91753117, 81322046, 81302698, 31671459, U1605221 and 2181001006, plus additional Chinese institutional research programs.
Competing interests
The authors declared no competing interests.

Study snapshot

DesignSmall-molecule discovery, biochemical/cellular target-validation and tumor-xenograft study.
ModelPurified SIRT6, human hepatocellular carcinoma cells and mouse xenograft models.
SamplePreclinical experiments; sample sizes vary by assay.
InterventionMDL-800, a selective allosteric SIRT6 activator.
DurationExperiment-dependent.
EndpointsSIRT6 deacetylase activation; H3K9ac and H3K56ac; HCC cell proliferation/cell cycle; tumor xenograft growth

What the study showed, in plain terms

This paper identified MDL-800, a selective small-molecule SIRT6 activator that worked inside cells. MDL-800 increased SIRT6 deacetylase activity, reduced H3K9/H3K56 acetylation and suppressed hepatocellular-carcinoma growth in preclinical models.

Key findings

MDL-800 activated SIRT6 by up to 22-fold in the reported biochemical system and became a widely used tool for studying pharmacological SIRT6 activation.

What this study can and cannot tell us

MDL-800 is an experimental research compound, not a dietary supplement, and these findings do not establish safety or efficacy in humans.

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Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability