SIRT6 is a deacetylase of histone H3 and inhibitors of SIRT6 have been thought as potential agents for treatment of diabetes. Herein we report the discovery of a series of new SIRT6 inhibitors containing the skeleton 1-phenylpiperazine. Among them, compound 5-(4-methylpiperazin-1-yl)-2-nitroaniline (6d) is the most potent one, which showed an IC₅₀ value of 4.93 μM against SIRT6 in the Fluor de Lys (FDL) assay. It displayed K_D values of 9.76 μM and 10 μM in surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) assays, respectively. In selectivity assay, 6d showed no activity against other members of the HDAC family (SIRT1-3 and HDAC1-11) at concentrations up to 200 µM. In a mouse model of type 2 diabetes, 6d could significantly increase the level of glucose transporter GLUT-1, thereby reducing blood glucose. Overall, this study provides a promising lead compound for subsequent drug discovery targeting SIRT6.

SIRT6是组蛋白H3的脱乙酰基酶，SIRT6抑制剂被认为是治疗糖尿病的潜在药物。在这里，我们报告发现了一系列新的含有骨架1-苯基哌嗪的SIRT6抑制剂。其中，化合物5-（4-甲基哌嗪-1-基）-2-硝基苯胺（6d）是最有效的化合物，在Fluor de Lys（FDL）分析中，相对于SIRT6的IC ₅₀值为4.93μM。在表面等离振子共振（SPR）和等温滴定量热（ITC）分析中，K _D值分别为9.76μM和10μM。在选择性分析中，当浓度高达200 µM时，6d对HDAC家族的其他成员（SIRT1-3和HDAC1-11）没有活性。在2型糖尿病的小鼠模型中，6d可显着增加葡萄糖转运蛋白GLUT-1的水平，从而降低血糖。总体而言，这项研究为随后针对SIRT6的药物发现提供了有希望的先导化合物。