PLK1 has an important role in the regulation of cell cycle and represents an important target for cancer treatment. This enzyme belongs to the Polo-like kinases family, which is characterized by a regulatory domain named Polo-box domain (PBD). Rather than regular kinase inhibitors, this domain provides high selectivity to PLK1. Here, we report on four novel PLK1 PBD inhibitors identified by cytotoxicity screening and fluorescence polarization assay of a chemical library of natural and semisynthetic compounds. These compounds revealed two- to three-fold higher selectivity to the PDB of PLK1 than to those of the related family members, PLK2 and PLK3. These four substances inhibited tumor cell growth of sensitive CCRF-CEM and multidrug-resistant CEM/ADR5000 leukemia cells. The tested compounds increased the apoptotic cell fraction, which indicates apoptosis as a major mechanism of cell death. Cell cycle analysis showed compound (5) arrested the cell cycle of CCRF-CEM cells in the G2/M phase, while the other three molecules ((compound (3), compound (4), and compound (6)) exerted pronounced cytotoxicity with an increase of cells in the sub-G1 population. Molecular docking was performed for the understanding of ligand-protein interaction, the tested candidates showed strong binding affinity to PLK1 PBD. In conclusion, we identified four new chemical scaffolds that may serve as lead compounds for the development of selective PLK1 inhibitors in the future.
Keywords: Apoptosis; Cell cycle; Drug screening; Neoplasms; Targeted chemotherapy, PLK.