The Discovery of Novel 10,11-Dihydro-5H-dibenz[b,f]azepine SIRT2 Inhibitors.
The Discovery of Novel 10,11-Dihydro-5H-dibenz[b,f]azepine SIRT2 Inhibitors.
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DOI：
10.1039/c2md00290f
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发表时间：
2012-03-01
期刊：
影响因子：
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通讯作者：
Fuchter MJ
中科院分区：
文献类型：
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作者：
Di Fruscia P;Ho KK;Laohasinnarong S;Khongkow M;Kroll SH;Islam SA;Sternberg MJ;Schmidtkunz K;Jung M;Lam EW;Fuchter MJ
Sirtuins（NAD+依赖性组蛋白脱乙酰酶）的亚型选择性抑制剂应该能够深入研究支持这些靶标的分子生物学以及它们在癌症和神经退行性疾病等疾病中如何失调。在此，我们展示了结构新颖的 SIRT2 抑制剂的发现。命中分子 8 是通过基于 10,11-二氢-5H-二苯并[b,f]氮杂卓支架的小分子化合物库的化学合成和生物表征发现的。体外筛选试验显示，化合物 8 针对 SIRT2 的 IC50 为 18 μM，并且与 SIRT1 相比，选择性高出 30 倍以上。对 MCF-7 细胞进行的细胞测定证实了体外选择性，并显示 hit 8 在浓度为 30 μM 时具有抗增殖活性。进行计算研究以预测 SIRT2 结合模式并合理化观察到的选择性。
Isoform selective inhibitors of the sirtuins (NAD+-dependent histone deacetylases) should enable an in depth study of the molecular biology underpinning these targets and how they are deregulated in diseases such as cancer and neurodegeneration. Herein, we present the discovery of structurally novel SIRT2 inhibitors. Hit molecule 8 was discovered through the chemical synthesis and biological characterization of a small-molecule compound library based around the 10,11-dihydro-5H-dibenz[b,f]azepine scaffold. In vitro screening assays revealed compound 8 to have an IC50 of 18 μM against SIRT2 and to exhibit more than 30-fold selectivity compared to SIRT1. Cellular assays, performed on MCF-7 cells, confirmed the in vitro selectivity and showed hit 8 to have antiproliferative activity at a concentration of 30 μM. Computational studies were performed to predict the SIRT2 binding mode and to rationalise the observed selectivity.