Discovery of Novel Polo-Like Kinase 1 Polo-Box Domain Inhibitors to Induce Mitotic Arrest in Tumor Cells

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• 作者：Tan Qin ; Fangjin Chen ; Xiaolong Zhuo ; Xiao Guo ; Taikangxiang Yun ; Ying Liu ; Chuanmao Zhang ; Luhua Lai
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：August 11, 2016
• 年：2016
• 卷：59
• 期：15
• 页码：7089-7096
• 全文大小：463K
• 年卷期：0
• ISSN：1520-4804

文摘

Polo-like kinase 1(Plk1) is vital for cell mitosis and has been identified as anticancer target. Its polo-box domain (PBD) mediates substrate binding, blocking of which may offer selective Plk1 inhibition compared to kinase domain inhibitors. Although several PBD inhibitors were reported, most of them suffer from low cell activity. Here, we report the discovery of novel inhibitors to induce mitotic arrest in HeLa cells by virtual screening with Plk1 PBD and cellular activity testing. Of the 81 compounds tested in the cell assay, 10 molecules with diverse chemical scaffolds are potent to induce mitotic arrest of HeLa at low micromolar concentrations. The best compound induces mitotic arrest of HeLa cells with an EC₅₀ of 4.4 μM. The cellular active inhibitors showed binding to Plk1 PBD and compete with PBD substrate in microscale thermophoresis analysis.