Clinical Research Division, Fred Hutchinson Cancer Research Center , 1100 Fairview Avenue North, Seattle, Washington 98109, United States.
J Med Chem. 2014 Apr 24;57(8):3283-94. doi: 10.1021/jm4018064. Epub 2014 Apr 15.
Sirtuins are a family of NAD(+)-dependent protein deacetylases that play critical roles in epigenetic regulation, stress responses, and cellular aging in eukaryotic cells. In an effort to identify small molecule inhibitors of sirtuins for potential use as chemotherapeutics as well as tools to modulate sirtuin activity, we previously identified a nonselective sirtuin inhibitor called cambinol (IC50 ≈ 50 μM for SIRT1 and SIRT2) with in vitro and in vivo antilymphoma activity. In the current study, we used saturation transfer difference (STD) NMR experiments with recombinant SIRT1 and 20 to map parts of the inhibitor that interacted with the protein. Our ongoing efforts to optimize cambinol analogues for potency and selectivity have resulted in the identification of isoform selective analogues: 17 with >7.8-fold selectivity for SIRT1, 24 with >15.4-fold selectivity for SIRT2, and 8 with 6.8- and 5.3-fold selectivity for SIRT3 versus SIRT1 and SIRT2, respectively. In vitro cytotoxicity studies with these compounds as well as EX527, a potent and selective SIRT1 inhibitor, suggest that antilymphoma activity of this compound class may be predominantly due to SIRT2 inhibition.
Sirtuins 是一类依赖 NAD(+)的蛋白去乙酰化酶，它们在真核细胞中的表观遗传调控、应激反应和细胞衰老中发挥着关键作用。为了寻找能够作为化疗药物以及调节 Sirtuins 活性的工具的 Sirtuins 小分子抑制剂，我们之前鉴定了一种非选择性的 Sirtuins 抑制剂，称为 cambinol（对 SIRT1 和 SIRT2 的 IC50 约为 50 μM），它具有体外和体内抗淋巴瘤活性。在本研究中，我们使用重组 SIRT1 和 20 的饱和转移差异（STD）NMR 实验来绘制与蛋白质相互作用的抑制剂部分。我们正在努力优化 cambinol 类似物的效力和选择性，已经鉴定出具有亚型选择性的类似物：17 对 SIRT1 的选择性超过 7.8 倍，24 对 SIRT2 的选择性超过 15.4 倍，8 对 SIRT3 的选择性分别为 SIRT1 和 SIRT2 的 6.8 倍和 5.3 倍。这些化合物的体外细胞毒性研究以及 EX527（一种有效的、选择性的 SIRT1 抑制剂）表明，这类化合物的抗淋巴瘤活性可能主要归因于 SIRT2 抑制。
