Lee Eun, An Ying, Kwon Junhee, Kim Keun Il, Jeon Raok
Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Cheongpa-ro 47-gil 100, Yongsan-gu, Seoul 04310, Republic of Korea.
Department of Biological Sciences, Sookmyung Women's University, Cheongpa-ro 47-gil 100, Yongsan-gu, Seoul 04310, Republic of Korea.
Bioorg Med Chem. 2017 Jul 15;25(14):3614-3622. doi: 10.1016/j.bmc.2017.04.004. Epub 2017 Apr 6.
A strong relationship between abnormal functions of Aurora kinases and tumorigenesis has been reported for decades. Consequently, Aurora kinases serve as potential targets for anticancer agents. Here, we identified aminobenzothiazole derivatives as novel inhibitors of Aurora B kinase through bioisosteric replacement of the previous inhibitors, aminobenzoxazole derivatives. Most of the urea-linked aminobenzothiazole derivatives showed potent and selective inhibitory activity against Aurora B kinase over Aurora A kinase. Molecular modeling indicated that compound 15g bound well to the active site of Aurora B kinase and formed the essential hydrogen bonds. The potent compounds, 15g and 15k, were selected, and their biological effects were evaluated using HeLa cell lines. It was found that these compounds inhibited the phosphorylation of histone H3 at Ser10 and induced G/M cell cycle arrest. We suggest that the reported compounds have the potential to be further developed as anticancer therapeutics.
几十年来，已有报道称极光激酶的异常功能与肿瘤发生之间存在密切关系。因此，极光激酶成为抗癌药物的潜在靶点。在此，我们通过对先前的抑制剂氨基苯并恶唑衍生物进行生物电子等排体替换，鉴定出氨基苯并噻唑衍生物为极光B激酶的新型抑制剂。大多数通过脲连接的氨基苯并噻唑衍生物对极光B激酶显示出比极光A激酶更强且更具选择性的抑制活性。分子模拟表明化合物15g与极光B激酶的活性位点结合良好，并形成了关键的氢键。我们选择了强效化合物15g和15k，并使用HeLa细胞系评估了它们的生物学效应。结果发现这些化合物抑制了组蛋白H3在Ser10位点的磷酸化，并诱导了G/M期细胞周期阻滞。我们认为所报道的这些化合物有潜力进一步开发成为抗癌治疗药物。
