Department of Oncology, Banyu Tsukuba Research Institute, Merck Research Laboratories, Tsukuba, Ibaraki, Japan.
Mol Cancer Ther. 2010 Jan;9(1):157-66. doi: 10.1158/1535-7163.MCT-09-0609. Epub 2010 Jan 6.
Aurora-A kinase is a one of the key regulators during mitosis progression. Aurora-A kinase is a potential target for anticancer therapies because overexpression of Aurora-A, which is frequently observed in some human cancers, results in aberrant mitosis leading to chromosomal instability and possibly tumorigenesis. MK-5108 is a novel small molecule with potent inhibitory activity against Aurora-A kinase. Although most of the Aurora-kinase inhibitors target both Aurora-A and Aurora-B, MK-5108 specifically inhibited Aurora-A kinase in a panel of protein kinase assays. Inhibition of Aurora-A by MK-5108 in cultured cells induced cell cycle arrest at the G(2)-M phase in flow cytometry analysis. The effect was confirmed by the accumulation of cells with expression of phosphorylated Histone H3 and inhibition of Aurora-A autophosphorylation by immunostaining assays. MK-5108 also induced phosphorylated Histone H3 in skin and xenograft tumor tissues in a nude rat xenograft model. MK-5108 inhibited growth of human tumor cell lines in culture and in different xenograft models. Furthermore, the combination of MK-5108 and docetaxel showed enhanced antitumor activities compared with control and docetaxel alone-treated animals without exacerbating the adverse effects of docetaxel. MK-5108 is currently tested in clinical trials and offers a new therapeutic approach to combat human cancers as a single agent or in combination with existing taxane therapies.
极光激酶 A 是有丝分裂进程中的关键调节因子之一。极光激酶 A 是一种潜在的抗癌治疗靶点，因为在一些人类癌症中经常观察到极光激酶 A 的过度表达，导致异常的有丝分裂，从而导致染色体不稳定，可能导致肿瘤发生。MK-5108 是一种新型小分子，对极光激酶 A 具有很强的抑制活性。尽管大多数极光激酶抑制剂都针对极光激酶 A 和极光激酶 B，但 MK-5108 在一系列蛋白激酶测定中特异性抑制极光激酶 A。MK-5108 在培养细胞中的抑制作用通过流式细胞术分析在 G2-M 期诱导细胞周期停滞得到证实。该作用通过免疫染色测定中磷酸化组蛋白 H3 的积累和极光激酶 A 自身磷酸化的抑制得到证实。MK-5108 还在裸鼠异种移植模型中的皮肤和异种移植肿瘤组织中诱导磷酸化组蛋白 H3。MK-5108 抑制培养的人类肿瘤细胞系和不同异种移植模型中的生长。此外，MK-5108 与多西他赛联合使用与对照和多西他赛单独治疗的动物相比，显示出增强的抗肿瘤活性，而没有加剧多西他赛的不良反应。MK-5108 目前正在临床试验中进行测试，作为单一药物或与现有的紫杉烷疗法联合使用，为治疗人类癌症提供了一种新的治疗方法。
