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Identification of a cellularly active SIRT6 allosteric activator


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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Data availability

Crystal structures and diffraction data have been deposited in the Protein Data Bank under accession codes PDB 5X16 (SIRT6-ADPR) and PDB 5Y2F (SIRT6–ADPR–MDL-801). All other data generated or analyzed during the study in this published article (and its supplementary information files) are available from the corresponding author on reasonable request.

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We sincerely thank D. Sinclair for discussion on activator application, and C. Steegborn and A. Mai for discussion on crystallization. We thank Z.-G. Han (Key Laboratory of Systems Biomedicine, Ministry of Education, and Collaborative Innovation Center of Systems Biomedicine of Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine) for providing cell lines. This work was supported in part by grants from the National Basic Research Program of China (973 Program) (2015CB910403 to J.Z. and G.C.), the National Natural Science Foundation of China (81721004 to G.C. and J.Z.; 91753117 to J.Z.; 81322046 to J.Z.; 81302698 to S.L.; 31671459 to Y.X.; U1605221 to H.L.; and 2181001006 to H.J.), the Program for Changjiang Scholars and the Innovative Research Team of the University of the Ministry Education of China (2017 to J.Z.), the CAS Interdisciplinary Innovation Team (2017 to J.Z.), the Innovation Program of the Shanghai Municipal Education Commission (2019 to J.Z.), the State Key Laboratory of Luminescence and application (SKLA-2016-12 to Y.X.), and the Strategic Priority Research Program of the Chinese Academy of Sciences, ‘Personalized Medicines—Molecular Signature-based Drug Discovery and Development’ (XDA12040100 to H.J.).

Author information

J. Zhang conceived and supervised the project. J. Zhang and Z.H. designed the experiments. Z.H., J. Zhao,Y.C., J.S., L.Z., C.W., H.H., J.X., J. Zhong, Q.Z., X.S., and Y.X. performed the biological experiments. J. Zhang, G.C.,Y.X., Z.H., S.L., and H.L. analyzed data. Z.H. and K.S. performed the crystallography. Y.C. and X.Y. carried out synthesis, purification, and characterization of compounds. W.D., S.L., B.H., J.M., H.H., M.T., X.S., Z.M., M.X., Y.E.C., and H.J. generated key protein reagents. K.S. solved the crystal structures. J. Zhang wrote the manuscript, and all other authors contributed specific parts of the manuscript; J. Zhang, G.C., and Y.X. assume responsibility for the manuscript in its entirety.

Competing interests

The authors declare no competing interests.

Correspondence to Ying Xu or Guoqiang Chen or Jian Zhang.

Supplementary information

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    Supplementary Figures 1–69 and Supplementary Tables 1–20

  2. Reporting Summary

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    Synthetic Procedures

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Further reading

Fig. 1: Discovery and biochemical characterization of MDL-800 and MDL-801 as activators of SIRT6 deacetylation.
Fig. 2: Cocrystal structure of MDL-801 bound to an allosteric site of SIRT6.
Fig. 3: MDL-800 induces H3K9ac and H3K56ac deacetylation and represses proliferation of HCC cells.
Fig. 4: MDL-800 arrests the cell cycle in HCC cells.
Fig. 5: MDL-800 activates SIRT6 deacetylation, thereby regulating the HCC cell cycle.
Fig. 6: MDL-800 inhibits xenograft tumor growth of HCC cells in immunocompromised mice.