Department of Pharmacology III, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu-Chong-Zhi Road, Shanghai 201203, China.
School of Life Sciences, Fudan University, Shanghai 200433, China.
Bioorg Med Chem Lett. 2014 Jul 15;24(14):3050-6. doi: 10.1016/j.bmcl.2014.05.028. Epub 2014 May 20.
SIRT1 is a NAD(+)-dependent deacetylase. It deacetylates a broad range of substrates and is involved in multiple diseases such as type 2 diabetes and cancer. Here we discovered a new class of SIRT1 inhibitors with the scaffold of 3-(furan-2-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole. The inhibitors up-regulate acetyl p53 level in human breast cells MCF-7. The docking simulations indicated that the scaffold and the R-substituents of the inhibitors bind in the C and D pocket of SIRT1, respectively, which was supported by the structure-activity relationship and SIRT1 mutagenesis studies. We propose that binding of the inhibitors repels the entering of the nicotinamide moiety of NAD(+) to the C pocket, prevents its transformation to the productive conformation and therefore inhibits the deacetylation catalyzed by SIRT1.
SIRT1 是一种依赖 NAD(+)的去乙酰化酶。它可以去乙酰化广泛的底物，并涉及多种疾病，如 2 型糖尿病和癌症。在这里，我们发现了一类新型的 SIRT1 抑制剂，其骨架为 3-(呋喃-2-基)-[1,2,4]三唑并[3,4-b][1,3,4]噻二唑。这些抑制剂可上调人乳腺癌细胞 MCF-7 中乙酰化 p53 的水平。对接模拟表明，抑制剂的骨架和 R-取代基分别与 SIRT1 的 C 口袋和 D 口袋结合，这得到了结构-活性关系和 SIRT1 突变研究的支持。我们提出，抑制剂的结合排斥了 NAD(+)的烟酰胺部分进入 C 口袋，阻止了其转化为有活性的构象，从而抑制了 SIRT1 催化的去乙酰化反应。
