Identification of a novel Polo-like kinase 1 inhibitor that specifically blocks the functions of Polo-Box domain.
Identification of a novel Polo-like kinase 1 inhibitor that specifically blocks the functions of Polo-Box domain.
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鉴定出一种新型 Polo 样激酶 1 抑制剂，可特异性阻断 Polo-Box 结构域的功能。
DOI：
10.18632/oncotarget.13603
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发表时间：
2017-01-03
期刊：
影响因子：
--
通讯作者：
Si S
中科院分区：
文献类型：
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作者：
Chen Y;Zhang J;Li D;Jiang J;Wang Y;Si S
Polo-like kinase1(Plk1)因其在细胞分裂中的重要作用而成为肿瘤治疗的重要靶点。Plk1除了含有一个高度保守的激酶结构域外，还含有一个Polo-Box结构域，这是Plk1的S亚细胞定位和有丝分裂功能所必需的。我们采用荧光偏振分析方法，从小分子化合物文库中鉴定出一个新的Plk1 PBD抑制剂T521。T521特异性抑制PLK1的PBD，但不抑制PLK2-3的PBD。T521与Plk1 PBD的部分赖氨酸残基发生共价结合，导致Plk1 PBD的二级结构发生显著变化。使用基于细胞的分析，我们发现T521阻碍了Plk1和Bub1之间的相互作用，Bub1是一种有丝分裂检查点蛋白。此外，经T521处理的HeLa细胞表现出明显的有丝分裂缺陷。重要的是，T521抑制了裸鼠移植瘤A549细胞的生长。综上所述，我们已经确定了一种新的Plk1抑制剂，它可以特异性地干扰Plk1 PBD的功能，并显示出抗癌活性。
Polo-like kinase 1 (Plk1) is a promising target for cancer therapy due to its essential role in cell division. In addition to a highly conserved kinase domain, Plk1 also contains a Polo-Box domain (PBD), which is essential for Plk1's subcellular localization and mitotic functions. We adopted a fluorescence polarization assay and identified a new Plk1 PBD inhibitor T521 from a small-molecule compound library. T521 specifically inhibits the PBD of Plk1, but not those of Plk2-3. T521 exhibits covalent binding to some lysine residues of Plk1 PBD, which causes significant changes in the secondary structure of Plk1 PBD. Using a cell-based assay, we showed that T521 impedes the interaction between Plk1 and Bub1, a mitotic checkpoint protein. Moreover, HeLa cells treated with T521 exhibited dramatic mitotic defects. Importantly, T521 suppresses the growth of A549 cells in xenograft nude mice. Taken together, we have identified a novel Plk1 inhibitor that specifically disrupts the functions of Plk1 PBD and shows anticancer activity.