SIRT6作用于组蛋白H3上特定赖氨酸(H3K9和H3K56)发挥去乙酰化酶活性，在生理条件下促进DNA修复、糖/脂代谢及延缓衰老，并在临床中发现对肝癌具有抑癌基因作用。然而，SIRT6调控的组蛋白乙酰化动态修饰在这些过程中的功能规律及其机制仍未阐明。我们在前期工作中发现了SIRT6首个可用于功能研究的小分子激动剂，其通过变构方式直接结合并激动SIRT6的去乙酰化酶活性。利用该探针，在肝癌细胞中我们证实激动SIRT6明显降低组蛋白H3K9和H3K56的乙酰化，并抑制肝癌细胞生长。本项目拟在此基础上，利用合理设计方法优化此类小分子结构，进一步获得高效高选择性的SIRT6组蛋白去乙酰化小分子激动剂，利用该化学探针工具系统揭示SIRT6调控的组蛋白乙酰化动态修饰在肝癌发生发展中的功能，阐明其调控机制及信号通路，为确定SIRT6作为潜在的抗肝癌新靶点提供理论依据，并发现相应的先导分子。

SIRT6, a member of deacetylase SIRT family, is responsible for deacetylation reactions of histone H3 Nε-acetyllysines 9 (H3K9Ac) and 56 (H3K56Ac). SIRT6 regulates diverse physiological processes, including genome stability, metabolism, and aging. As a tumor suppressor, SIRT6 is frequently reduced for its expressions in human hepatocellular carcinoma (HCC). However, the function and mechanism of these physiological and pathological processes remain unknown. In our previous study, we identified a SIRT6 activator MDL-800, which activated the deacetylase activity of SIRT6 by binding to a potential allosteric site, leading to a global decrease in H3K9Ac and H3K56Ac in HCC cells. The current project, based on our previous work, plans to further improve the deacetylase activity and selectivity of this series of SIRT6 activators. Using the optimized SIRT6 activator as a probe, the dynamic modification of histone H3K9 and H3K56 in HCC will be explored for its role in function effect, molecular mechanism, and signaling pathway. These data are beneficial to demonstrate that pharmacological activation of SIRT6 is a valid therapeutic approach for the treatment of HCC, and provides a first-in-class cellularly active small-molecule SIRT6 activator as lead compounds.