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J Med Chem. 2016 Aug 11;59(15):7089-96. doi: 10.1021/acs.jmedchem.6b00261. Epub 2016 Jul 26.

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

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BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University , Beijing, 100871, China.
Center for Quantitative Biology, Peking University , Beijing, 100871, China.
The Ministry of Education Key Laboratory of Cell Proliferation and Differentiation and the State Key Laboratory of Membrane Biology, College of Life Sciences, Peking University , Beijing, 100871, China.


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.

[Indexed for MEDLINE]

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