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

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.