Zhang Leilei, Yang Tianming, Xie Xilei, Liu Gang
Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Tsinghua-Peking Center for Life Sciences, China; Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Haidian Dist., Beijing 100084, China.
Bioorg Med Chem Lett. 2015 Aug 1;25(15):2937-42. doi: 10.1016/j.bmcl.2015.05.043. Epub 2015 Jun 2.
Aurora B kinase plays an important role in the cell normal mitosis and overexpresses in a variety of tumors. Inhibition of Aurora B kinase resulted in an apoptosis of cancer cells, which prevented tumor growth in xenograft models. In this Letter, we developed a luminescent kinase assay to perform high-throughput screening for identification of small molecule Aurora B inhibitors. Two 3,5,6-substituted indolin-2-one derivatives were identified within an in-house compound library. Their new derivatives were then designed and synthesized that resulting two new inhibitors of Aurora B kinase with improved potency. Docking simulation further demonstrated the proposed binding modes between indolin-2-one inhibitor and Aurora B.
极光B激酶在细胞正常有丝分裂中起重要作用，且在多种肿瘤中过表达。抑制极光B激酶会导致癌细胞凋亡，这在异种移植模型中可阻止肿瘤生长。在本信函中，我们开发了一种发光激酶测定法，用于进行高通量筛选以鉴定小分子极光B抑制剂。在一个内部化合物库中鉴定出了两种3,5,6-取代的吲哚啉-2-酮衍生物。然后设计并合成了它们的新衍生物，得到了两种活性增强的新型极光B激酶抑制剂。对接模拟进一步证明了吲哚啉-2-酮抑制剂与极光B之间的假定结合模式。
