Identification of inhibitors of the polo-box domain of polo-like kinase 1 from natural and semisynthetic compounds

  • Sara Abdelfatah
  • Edmond Fleischer
  • Anette Klinger
  • Vincent Kam Wai Wong
  • Thomas EfferthEmail author


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.


Apoptosis Cell cycle Drug screening Neoplasms Targeted chemotherapy, PLK 



cyclin-dependent kinase


50% inhibition concentration


Polo-box domain


Polo-box cap


Polo-like kinase


death-associated kinase 2



We extend our thanks to Angela Berg (Leipzig University) for analysing compound activities in fluorescence polarization assays.


Fluorescence polarization assays work was supported by the Deutsche Forschungsgemeinschaft (INST 268/281–1 FUGG). S.A. is grateful to the German Academic Exchange Service (DAAD) for a PhD stipend.

Compliance with ethical standards

Conflict of interest

Sara Abdelfatah declares that she has no conflict of interest. Edmond Fleisher declares that he has no conflict of interest. Annette Klinger declares that she has no conflict of interest. Vincent K. W. Wong declares that he has no conflict of interest. Thomas Efferth declares that he has no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

For this type of study, formal consent is not required.


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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmaceutical Biology, Institute of Pharmacy and BiochemistryJohannes Gutenberg UniversityMainzGermany
  2. 2.MicroCombiChem GmbHWiesbadenGermany
  3. 3.State Key Laboratory of Quality Research in Chinese MedicineMacau University of Science and TechnologyMacauChina

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