Sirtuin inhibitors have attracted much interest due to the involvement of sirtuins in various biological processes. Several SIRT2‐selective inhibitors have been developed, and some exhibit anticancer activities. To facilitate the choice of inhibitors in future studies and the development of better inhibitors, we directly compared several reported SIRT2‐selective inhibitors: AGK2, SirReal2, Tenovin‐6, and TM. In vitro, TM is the most potent and selective inhibitor, and only TM could inhibit the demyristoylation activity of SIRT2. SirReal2, Tenovin‐6, and TM all showed cytotoxicity in cancer cell lines, with Tenovin‐6 being the most potent, but only TM showed cancer‐cell‐specific toxicity. All four compounds inhibited the anchorage‐independent growth of HCT116 cells, but the effect of TM was most significantly affected by SIRT2 overexpression, suggesting that the anticancer effect of TM depends more on SIRT2 inhibition. These results not only provide useful guidance about choosing the right SIRT2 inhibitor in future studies, but also suggest general practices that should be followed for small‐molecule inhibitor development activities.

中文翻译：

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SIRT2抑制剂的直接比较：效力，特异性，活性依赖性抑制和针对靶点的抗癌活性

由于Sirtuin参与各种生物过程，Sirtuin抑制剂引起了人们的极大兴趣。已经开发了几种SIRT2选择性抑制剂，有些具有抗癌活性。为了方便将来研究中抑制剂的选择和开发更好的抑制剂，我们直接比较了几种报道的SIRT2选择性抑制剂：AGK2，SirReal2，Tenovin-6和TM。在体外，TM是最有效和选择性的抑制剂，只有TM可以抑制SIRT2的脱豆肉芽糖化活性。SirReal2，Tenovin-6和TM在癌细胞系中均显示出细胞毒性，其中Tenovin-6是最有效的，但只有TM显示出癌细胞特异性毒性。所有这四种化合物均抑制HCT116细胞的锚定非依赖性生长，但TM的作用受SIRT2过表达的影响最大，提示TM的抗癌作用更多地取决于SIRT2抑制。这些结果不仅为将来的研究中选择合适的SIRT2抑制剂提供了有用的指导，而且还建议了小分子抑制剂开发活动应遵循的一般做法。