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

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Summary

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.

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Abbreviations

CDK:

cyclin-dependent kinase

IC50 :

50% inhibition concentration

PBD:

Polo-box domain

PC:

Polo-box cap

PLK:

Polo-like kinase

DAPK-2:

death-associated kinase 2

References

  1. Van Vugt MATM, Medema RH (2005) Getting in and out of mitosis with polo-like kinase-1. Oncogene 24:2844–2859

    PubMed  Google Scholar 

  2. Moshe Y, Boulaire J, Pagano M, Hershko A (2004) Role of polo-like kinase in the degradation of early mitotic inhibitor 1, a regulator of the anaphase promoting complex/cyclosome. Proc Natl Acad Sci U S A 101:7937–7942

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Lowery DM, Lim D, Yaffe MB (2005) Structure and function of polo-like kinases. Oncogene 24:248–259

    CAS  PubMed  Google Scholar 

  4. Seki A, Coppinger J a, Jang C-Y et al (2008) Bora and the kinase Aurora a cooperatively activate the kinase Plk1 and control mitotic entry. Science 320:1655–1658

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Ohkura H, Hagan IM, Glover DM (1995) The conserved Schizosaccharomyces pombe kinase plol , required to form a bipolar. Genes Dev:1059–1073

  6. Lane HA, Nigg EA (1996) Antibody microinjection reveals an essential role for human polo-like kinase 1 (Plk1) in the functional maturation of mitotic centrosomes. J Cell Biol 135:1701–1713

    CAS  PubMed  Google Scholar 

  7. Nigg EA (1998) Polo-like kinases: positive regulators of cell division from start to finish. Curr Opin Cell Biol 10:776–783

    CAS  PubMed  Google Scholar 

  8. Sanhaji M, Ritter A, Belsham HR et al (2014) Polo-like kinase 1 regulates the stability of the mitotic centromere-associated kinesin in mitosis. Oncotarget 5:3130–3144

    PubMed  PubMed Central  Google Scholar 

  9. Weichert W, Ullrich A, Schmidt M et al (2006) Expression patterns of polo-like kinase 1 in human gastric cancer. Cancer Sci 97:271–276

    CAS  PubMed  Google Scholar 

  10. Li H, Wang H, Sun Z et al (2017) The clinical and prognostic value of polo-like kinase 1 in lung squamous cell carcinoma patients: immunohistochemical analysis. Biosci Rep 37:BSR20170852

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Schöffski P (2009) Polo-like kinase (PLK) inhibitors in preclinical and early clinical development in oncology. Oncologist 14:559–570

    PubMed  Google Scholar 

  12. Berg A, Berg T (2016) Inhibitors of the polo-box domain of polo-like kinase 1. Chem Bio Chem 17:650–656

    CAS  PubMed  Google Scholar 

  13. Rudolph D, Steegmaier M, Hoffmann M et al (2009) BI 6727, a polo-like kinase inhibitor with improved pharmacokinetic profile and broad antitumor activity. Clin Cancer Res 15:3094–3102

    CAS  PubMed  Google Scholar 

  14. Raab M, Pachl F, Kramer A et al (2014) Quantitative chemical proteomics reveals a Plk1 inhibitor-compromised cell death pathway in human cells. Cell Res 24:1141–1145

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Liu X (2015) Targeting polo-like kinases: a promising therapeutic approach for Cancer treatment. Transl Oncol 8:185–195

    PubMed  PubMed Central  Google Scholar 

  16. García-Alvarez B, de Cárcer G, Ibañez S et al (2007) Molecular and structural basis of polo-like kinase 1 substrate recognition: implications in centrosomal localization. Proc Natl Acad Sci U S A 104:3107–3112

    PubMed  PubMed Central  Google Scholar 

  17. Liu F, Park JE, Qian WJ et al (2012) Identification of high affinity polo-like kinase 1 (Plk1) polo-box domain binding peptides using oxime-based diversification. ACS Chem Biol 7:805–810

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Elia AEH, Rellos P, Haire LF et al (2003) The molecular basis for phosphodependent substrate targeting and regulation of Plks by the polo-box domain. Cell 115:83–95

    CAS  PubMed  Google Scholar 

  19. Mann J (2002) Natural products in cancer chemotherapy: past, present and future. Nat Rev Cancer 2:143–148

    CAS  PubMed  Google Scholar 

  20. Johnson IS, Armstrong JG, Gorman M, Burnett JP (1963) The Vinca alkaloids: a new class of oncolytic agents. Cancer Res 23:1390–1427

    CAS  PubMed  Google Scholar 

  21. Demain AL, Vaishnav P (2011) Natural products for cancer chemotherapy. Microb Biotechnol 4:687–699

    PubMed  PubMed Central  Google Scholar 

  22. Yin Z, Song Y, Rehse PH (2013) Thymoquinone blocks pSer/pThr recognition by plk1 polo-box domain as a phosohate mimic. ACS Chem Biol 8:303–308

    CAS  PubMed  Google Scholar 

  23. Zhang G, Zhang Z, Liu Z (2013) Scytonemin inhibits cell proliferation and arrests cell cycle through downregulating Plk1 activity in multiple myeloma cells. Tumor Biol 34:2241–2247

    CAS  Google Scholar 

  24. Hamdoun S, Fleischer E, Klinger A, Efferth T (2017) Lawsone derivatives target the Wnt/β-catenin signaling pathway in multidrug-resistant acute lymphoblastic leukemia cells. Biochem Pharmacol 146:63–73

    CAS  PubMed  Google Scholar 

  25. Saeed M, Kuete V, Kadioglu O et al (2014) Cytotoxicity of the bisphenolic honokiol from Magnolia officinalis against multiple drug-resistant tumor cells as determined by pharmacogenomics and molecular docking. Phytomedicine 21:1525–1533

    CAS  PubMed  Google Scholar 

  26. Kuete V, Mbaveng AT, Sandjo LP et al (2017) Cytotoxicity and mode of action of a naturally occurring naphthoquinone, 2-acetyl-7-methoxynaphtho[2,3-b]furan-4,9-quinone towards multi-factorial drug-resistant cancer cells. Phytomedicine 33:62–68

    CAS  PubMed  Google Scholar 

  27. Reindl W, Yuan J, Krämer A et al (2008) Inhibition of polo-like kinase 1 by blocking polo-box domain-dependent protein-protein interactions. Chem Biol 15:459–466

    CAS  PubMed  Google Scholar 

  28. Reindl W, Strebhardt K, Berg T (2008) A high-throughput assay based on fluorescence polarization for inhibitors of the polo-box domain of polo-like kinase 1. Anal Biochem 383:205–209

    CAS  PubMed  Google Scholar 

  29. Reindl W, Gräber M, Strebhardt K, Berg T (2009) Development of high-throughput assays based on fluorescence polarization for inhibitors of the polo-box domains of polo-like kinases 2 and 3. Anal Biochem 395:189–194

    CAS  PubMed  Google Scholar 

  30. Sakkiah S, Senese S, Yang Q et al (2014) Dynamic and multi-pharmacophore modeling for designing polo-box domain inhibitors. PLoS One 9:1–9

    Google Scholar 

  31. Scharow A, Raab M, Saxena K et al (2015) Optimized Plk1 PBD inhibitors based on Poloxin induce mitotic arrest and apoptosis in tumor cells. ACS Chem Biol 10:2570–2579

    CAS  PubMed  Google Scholar 

  32. Lapenna S, Giordano A (2009) Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov 8:547–566

    CAS  PubMed  Google Scholar 

  33. Strebhardt K (2010) Multifaceted polo-like kinases: drug targets and antitargets for cancer therapy. Nat Rev Drug Discov 9:643–660

    CAS  PubMed  Google Scholar 

  34. Strebhardt K, Ullrich A (2006) Targeting polo-like kinase 1 for cancer therapy. Nat Rev Cancer 6:321–330

    CAS  PubMed  Google Scholar 

  35. Liu X, Lei M, Erikson RL (2006) Normal cells , but not Cancer cells , survive severe Plk1 depletion. Mol Cell Biol 26:2093–2108

    PubMed  PubMed Central  Google Scholar 

  36. Lei M, Erikson RL (2008) Plk1 depletion in nontransformed diploid cells activates the DNA-damage checkpoint. Oncogene 27:3935–3943

    CAS  PubMed  Google Scholar 

  37. Yuan J, Sanhaji M, Krmer A et al (2011) Polo-box domain inhibitor poloxin activates the spindle assembly checkpoint and inhibits tumor growth in vivo. Am J Pathol 179:2091–2099

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Qin T, Chen F, Zhuo X et al (2016) Discovery of novel polo-like kinase 1 polo-box domain inhibitors to induce mitotic arrest in tumor cells. J Med Chem 59:7089–7096

    CAS  PubMed  Google Scholar 

  39. Shan HM, Shi Y, Quan J (2015) Identification of green tea Catechins as potent inhibitors of the polo-box domain of polo-like kinase 1. ChemMedChem 10:158–163

    CAS  PubMed  Google Scholar 

  40. Chen Y, Zhang J, Li D et al (2016) Identification of a novel polo-like kinase 1 inhibitor that specifically blocks the functions of polo-box domain. Oncotarget 8:1234–1246

    PubMed Central  Google Scholar 

  41. Syed N, Smith P, Sullivan A et al (2006) Transcriptional silencing of polo-like kinase 2 ( SNK / PLK2 ) is a frequent event in B-cell malignancies. Blood 107:250–256

    CAS  PubMed  Google Scholar 

  42. Yang Y, Bai J, Shen R et al (2008) Polo-like kinase 3 functions as a tumor suppressor and is a negative regulator of hypoxia-inducible factor-1?? Under hypoxic conditions. Cancer Res 68:4077–4085

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Brożek J, Bryl E, Płoszyńska A et al (2009) P-glycoprotein activity predicts outcome in childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol 31:493–499

    PubMed  Google Scholar 

  44. Dhooge C, De Moerloose B, Laureys G et al (1999) P-glycoprotein is an independent prognostic factor predicting relapse in childhood acute lymphoblastic leukaemia: results of a 6-year prospective study. Br J Haematol 105:676–683

    CAS  PubMed  Google Scholar 

  45. Wu CP, Hsieh CH, Hsiao SH et al (2015) Human ATP-binding cassette transporter ABCB1 confers resistance to Volasertib (BI 6727), a selective inhibitor of polo-like kinase 1. Mol Pharm 12:3885–3895

    CAS  PubMed  Google Scholar 

  46. Ferrarotto R, Goonatilake R, Young Yoo S et al (2016) Epithelial-mesenchymal transition predicts polo-like kinase 1 inhibitor-mediated apoptosis in non-small cell lung Cancer. Clin Cancer Res 22:1674–1686

    CAS  PubMed  Google Scholar 

  47. Mailand N, Bekker-Jensen S, Bartek J, Lukas J (2006) Destruction of Claspin by SCFbTrCP restrains Chk1 activation and facilitates recovery from genotoxic stress. Mol Cell 23:307–318

    CAS  PubMed  Google Scholar 

  48. Elowe S, Hümmer S, Uldschmid A et al (2007) On BubR1 regulates the stability of kinetochore – microtubule interactions. Genes Dev 21:2205–2219

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Peters U, Cherian J, Kim JH et al (2006) Probing cell-division phenotype space and polo-like kinase function using small molecules. Nat Chem Biol 2:618–626

    CAS  PubMed  Google Scholar 

  50. Elia AEH (2003) Proteomic screen finds pSer/pThr-binding domain localizing Plk1 to mitotic substrates. Science 299(80):1228–1231

    CAS  PubMed  Google Scholar 

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Acknowledgements

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

Funding

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.

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Authors and Affiliations

  1. Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, 55128, Mainz, Germany

    Sara Abdelfatah & Thomas Efferth

  2. MicroCombiChem GmbH, Wiesbaden, Germany

    Edmond Fleischer & Anette Klinger

  3. State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China

    Vincent Kam Wai Wong

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  1. Sara Abdelfatah
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  2. Edmond Fleischer
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  5. Thomas Efferth
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Correspondence to Thomas Efferth.

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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.

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Abdelfatah, S., Fleischer, E., Klinger, A. et al. Identification of inhibitors of the polo-box domain of polo-like kinase 1 from natural and semisynthetic compounds. Invest New Drugs 38, 1–9 (2020). https://doi.org/10.1007/s10637-019-00752-0

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