Polo‑like Kinase 1 as a Target for Anti‑tumor Therapy

Authors: I. Procházková;  B. Vojtěšek
Authors‘ workplace: Regionální centrum aplikované molekulární onkologie, Masarykův onkologický ústav, Brno
Published in: Klin Onkol 2015; 28(Supplementum 2): 32-39
doi: 10.14735/amko20152S32


Individual proteins from polo-like kinase (Plk) family fulfil different but critical functions in regulating cell cycle and coordinate cell response to DNA  damage. The most studied one from this five  member family is Plk1. It is a serine/ threonine kinase that plays a pivotal role in many aspects of mitosis and its deregulation is common in various tumor types where the elevated level is mostly associated with worse prognosis. From the therapeutical point of view, intertwin­ed relationship between Plk1 and p53 protein is very interesting and will be discussed. Not only for these reasons, Plk1 has become an attractive target for anti‑tumor drug development. The most promising seems to be ATP binding site inhibitor Volasertib (BI 6727) which provided a survival benefit for patients with acute myeloid leukemia and is now tested in phase III clinical trial. A new generation of Plk1 inhibitors that target the second druggable domain of Plk1, the polo- box domain, is currently being tested preclinically and are believed to improve Plk1 specificity.

Key words:
polo like kinase 1 –  tumor suppressor protein p53 –  ATP  competitive inhibitors –  polo- box domain –  drug evaluation studies

This study was supported by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101), MEYS – NPS I – LO1413, MH CZ – DRO (MMCI, 00209805) and BBMRI_CZ (LM2010004).

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.

9. 4. 2015

19. 6. 2015


1. Burns TF, Fei P, Scata KA et al. Silencing of the novel p53 target gene Snk/ Plk2 leads to mitotic catastrophe in paclitaxel (taxol)- exposed cells. Mol Cell Biol 2003; 23(16): 5556– 5571.

2. Warnke S, Kemmler S, Hames RS et al. Polo‑like kinase‑ 2 is required for centriole duplication in mammalian cells. Curr Biol CB 2004; 14(13): 1200– 1207.

3. Matthew EM, Yen TJ, Dicker DT et al. Replication stress, defective S‑ phase checkpoint and increased death in Plk2- deficient human cancer cells. Cell Cycle Georget Tex 2007; 6(20): 2571– 2578.

4. Syed N, Smith P, Sullivan A et al. Transcriptional silenc­ing of polo‑like kinase 2 (SNK/ PLK2) is a frequent event in B‑ cell malignancies. Blood 2006; 107(1): 250– 256.

5. Wang Q, Xie S, Chen J et al. Cell cycle arrest and apoptosis induced by human polo‑like kinase 3 is mediated through perturbation of microtubule integrity. Mol Cell Biol 2002; 22(10): 3450– 3459.

6. Xie S, Wu H, Wang Q et al. Plk3 functionally links DNA damage to cell cycle arrest and apoptosis at least in part via the p53 pathway. J Biol Chem 2001; 276(46): 43305– 43312.

7. Xu D, Yao Y, Jiang X et al. Regulation of PTEN stability and activity by Plk3. J Biol Chem 2010; 285(51): 39935– 39942. doi: 10.1074/ jbc.M110.166462.

8. Winkles JA, Alberts GF. Differential regulation of polo‑like kinase 1, 2, 3, and 4 gene expression in mammalian cells and tissues. Oncogene 2005; 24(2): 260– 266.

9. Swallow CJ, Ko MA, Siddiqui NU et al. Sak/ Plk4 and mitotic fidelity. Oncogene 2005; 24(2): 306– 312.

10. Bonni S, Ganuelas ML, Petrinac S et al. Human Plk4 phosphorylates Cdc25C. Cell Cycle Georget Tex 2008; 7(4): 545– 547.

11. Macmillan JC, Hudson JW, Bull S et al. Comparative expression of the mitotic regulators SAK and PLK in colorectal cancer. Ann Surg Oncol 2001; 8(9): 729– 740.

12. Mason J, Wei S, Luo X et al. Inhibition of polo‑like kinase 4 as an anti‑cancer strategy. Cancer Res 2011; 71 (Suppl 8): abstr. LB‑ 215.

13. Laufer R, Forrest B, Li S‑ W et al. The discovery of PLK4 inhibitors: (E)- 3- ((1H‑ Indazol‑ 6- yl)methylene)indolin‑2- ones as novel antiproliferative agents. J Med Chem 2013; 56(15): 6069– 6087. doi: 10.1021/ jm400380m.

14. Andrysik Z, Bernstein WZ, Deng L et al. The novel mouse polo‑like kinase 5 responds to DNA damage and localizes in the nucleolus. Nucleic Acids Res 2010; 38(9): 2931– 2943. doi: 10.1093/ nar/ gkq011.

15. De Cárcer G, Manning G, Malumbres M. From Plk1 to Plk5: functional evolution of polo‑like kinases. Cell Cycle Georget Tex 2011; 10(14): 2255– 2262.

16. de Cárcer G, Escobar B, Higuero AM et al. Plk5, a polo box domain‑only protein with specific roles in neuron dif­ferentiation and glioblastoma suppression. Mol Cell Biol 2011; 31(6): 1225– 1239. doi: 10.1128/ MCB.00607‑ 10.

17. Golsteyn RM, Schultz SJ, Bartek J et al. Cell cycle analysis and chromosomal localization of human Plk1, a putative homologue of the mitotic kinases Drosophila polo and Saccharomyces cerevisiae Cdc5. J Cell Sci 1994; 107(6): 1509– 1517.

18. Toyoshima‑ Morimoto F, Taniguchi E, Shinya N et al. Polo‑like kinase 1 phosphorylates cyclin B1 and targets it to the nucleus during prophase. Nature 2001; 410(6825): 215– 220.

19. Kumagai A, Dunphy WG. Purification and molecular cloning of Plx1, a Cdc25- regulatory kinase from Xenopus egg extracts. Science 1996; 273(5280): 1377– 1380.

20. Abrieu A, Brassac T, Galas S et al. The Polo‑like kinase Plk1 is a component of the MPF amplification loop at the G2/ M‑ phase transition of the cell cycle in Xenopus eggs. J Cell Sci 1998; 111(12): 1751– 1757.

21. Toyoshima‑ Morimoto F, Taniguchi E, Nishida E. Plk1 promotes nuclear translocation of human Cdc25C during prophase. EMBO Rep 2002; 3(4): 341– 348.

22. Casenghi M, Meraldi P, Weinhart U et al. Polo‑like kinase 1 regulates Nlp, a centrosome protein involved in microtubule nucleation. Dev Cell 2003; 5(1): 113– 125.

23. Li H, Liu XS, Yang X et al. Polo‑like kinase 1 phosphorylation of p150Glued facilitates nuclear envelope breakdown during prophase. Proc Natl Acad Sci U S A 2010; 107(33): 14633– 14638. doi: 10.1073/ pnas.1006615107.

24. Li H, Liu XS, Yang X et al. Phosphorylation of CLIP‑ 170 by Plk1 and CK2 promotes timely formation of kinetochore‑microtubule attachments. EMBO J 2010; 29(17): 2953– 2965. doi: 10.1038/ emboj.2010.174.

25. Liu XS, Song B, Tang J et al. Plk1 phosphorylates Sgt1 at the kinetochores to promote timely kinetochore‑microtubule attachment. Mol Cell Biol 2012; 32(19): 4053– 4067. doi: 10.1128/ MCB.00516‑ 12.

26. Hansen DV, Loktev AV, Ban KH et al. Plk1 regulates activation of the anaphase promoting complex by phosphorylat­ing and triggering SCFbetaTrCP‑ dependent destruction of the APC Inhibitor Emi1. Mol Biol Cell 2004; 15(12): 5623– 5634.

27. Yoo HY, Kumagai A, Shevchenko A et al. Adaptation of a DNA replication checkpoint response depends upon inactivation of claspin by the polo‑like kinase. Cell 2004; 117(5): 575– 588.

28. Mamely I, van Vugt MA, Smits VA et al. Polo‑like kinase‑ 1 controls proteasome‑ dependent degradation of Claspin during checkpoint recovery. Curr Biol CB 2006; 16(19): 1950– 1955.

29. Liu X, Lei M, Erikson RL. Normal cells, but not cancer cells, survive severe Plk1 depletion. Mol Cell Biol 2006; 26(6): 2093– 2108.

30. Clay FJ, McEwen SJ, Bertoncello I et al. Identification and cloning of a protein kinase‑ encoding mouse gene, Plk, related to the polo gene of drosophila. Proc Natl Acad Sci U S A 1993; 90(11): 4882– 4886.

31. Yim H, Erikson RL. Plk1‑ targeted therapies in TP53-  or RAS‑ mutated cancer. Mutat Res Rev Mutat Res 2014; 761: 31– 39. doi: 10.1016/ j.mrrev.2014.02.005.

32. Archambault V, Lépine G, Kachaner D. Understanding the polo kinase machine. Oncogene. In press 2015. doi: 10.1038/ onc.2014.451.

33. Hyun SY, Hwang HI, Jang YJ. Polo‑like kinase‑ 1 in DNA damage response. BMB Rep 2014; 47(5): 249– 255.

34. Song B, Liu XS, Liu X. Polo‑like kinase 1 (Plk1): an Unexpected Player in DNA Replication. Cell Div 2012; 7: 3. doi: 10.1186/ 1747‑ 1028‑ 7‑ 3.

35. Yim H, Erikson RL. Polo‑like kinase 1 depletion induces DNA damage in early S prior to caspase activation. Mol Cell Biol 2009; 29(10): 2609– 2621. doi: 10.1128/ MCB.01277‑ 08.

36. Li H, Wang Y, Liu X. Plk1‑ dependent phosphorylation regulates functions of DNA topoisomerase II alpha in cell cycle progression. J Biol Chem 2008; 283(10): 6209– 6221. doi: 10.1074/ jbc.M709007200.

37. Shen M, Cai Y, Yang Y et al. Centrosomal protein FOR20 is essential for S‑ phase progression by recruiting Plk1 to centrosomes. Cell Res 2013; 23(11): 1284– 1295. doi: 10.1038/ cr.2013.127.

38. Tsvetkov L, Stern DF. Interaction of chromatin‑associated Plk1 and Mcm7. J Biol Chem 2005; 280(12): 11943– 11947.

39. Wolf G, Elez R, Doermer A et al. Prognostic significance of polo‑like kinase (PLK) expression in non‑small cell lung cancer. Oncogene 1997; 14(5): 543– 549.

40. Knecht R, Oberhauser C, Strebhardt K. PLK (polo‑like kinase), a new prognostic marker for oropharyngeal carcinomas. Int J Cancer J Int Cancer 2000; 89(6): 535– 536.

41. Knecht R, Elez R, Oechler M et al. Prognostic significance of polo‑like kinase (PLK) expression in squamous cell carcinomas of the head and neck. Cancer Res 1999; 59(12): 2794– 2797.

42. Tokumitsu Y, Mori M, Tanaka S et al. Prognostic significance of polo‑like kinase expression in esophageal carcinoma. Int J Oncol 1999; 15(4): 687– 692.

43. Weichert W, Kristiansen G, Winzer KJ et al. Polo‑like kinase isoforms in breast cancer: expression patterns and prognostic implications. Virchows Arch 2005; 446(4): 442– 450.

44. Wolf G, Hildenbrand R, Schwar C et al. Polo‑like kinase: a novel marker of proliferation: correlation with estrogen‑ receptor expression in human breast cancer. Pathol Res Pract 2000; 196(11): 753– 759.

45. King SI, Purdie CA, Bray SE et al. Immunohistochemical detection of polo‑like kinase‑ 1 (PLK1) in primary breast cancer is associated with TP53 mutation and poor clinical outcome. Breast Cancer Res BCR 2012; 14(2): R40.

46. Pellegrino R, Calvisi DF, Ladu S et al. Oncogenic and tumor suppressive roles of polo‑like kinases in human hepatocellular carcinoma. Hepatol Baltim Md 2010; 51(3): 857– 868. doi: 10.1002/ hep.23467.

47. Weichert W, Schmidt M, Jacob J et al. Overexpression of polo‑like kinase 1 is a common and early event in pancreatic cancer. Pancreatol 2005; 5(2– 3): 259– 265.

48. Gray PJ Jr, Bearss DJ, Han H et al. Identification of human polo‑like kinase 1 as a potential therapeutic target in pancreatic cancer. Mol Cancer Ther 2004; 3(5): 641– 646.

49. Weichert W, Schmidt M, Gekeler V et al. Polo‑like kinase 1 is overexpressed in prostate cancer and linked to higher tumor grades. Prostate 2004; 60(3): 240– 245.

50. Weichert W, Kristiansen G, Schmidt M et al. Polo‑like kinase 1 expression is a prognostic factor in human colon cancer. World J Gastroenterol 2005; 11(36): 5644– 5650.

51. Takai N, Miyazaki T, Fujisawa K et al. Polo‑like kinase (PLK) expression in endometrial carcinoma. Cancer Lett 2001; 169(1): 41– 49.

52. Takai N, Miyazaki T, Fujisawa K et al. Expression of polo‑like kinase in ovarian cancer is associated with histological grade and clinical stage. Cancer Lett 2001; 164(1): 41– 49.

53. Weichert W, Denkert C, Schmidt M et al. Polo‑like kinase isoform expression is a prognostic factor in ovarian carcinoma. Br J Cancer 2004; 90(4): 815– 821.

54. Nigro JM, Baker SJ, Preisinger AC et al. Mutations in the p53 gene occur in diverse human tumour types. Nature 1989; 342(6250): 705– 708.

55. Vogelstein B, Lane D, Levine AJ. Surfing the p53 net­work. Nature 2000; 408(6810): 307– 310.

56. Brown CJ, Lain S, Verma CS et al. Awakening guardian angels: drugging the p53 pathway. Nat Rev Cancer 2009; 9(12): 862– 873. doi: 10.1038/ nrc2763.

57. Lane DP. Cancer. p53, guardian of the genome. Nature 1992; 358(6381): 15– 16.

58. Junttila MR, Evan GI. p53 –  a Jack of all trades but master of none. Nat Rev Cancer 2009; 9(11): 821– 829. doi: 10.1038/ nrc2728.

59. Bode AM, Dong Z. Post‑translational modification of p53 in tumorigenesis. Nat Rev Cancer 2004; 4(10): 793– 805.

60. Cheok CF, Verma CS, Baselga J et al. Translating p53 into the clinic. Nat Rev Clin Oncol 2011; 8(1): 25– 37. doi: 10.1038/ nrclinonc.2010.174.

61. Zhu H, Chang BD, Uchiumi T et al. Identification of promoter elements responsible for transcriptional inhibition of polo‑like kinase 1 and topoisomerase II alpha genes by p21(WAF1/ CIP1/ SDI1). Cell Cycle 2002; 1(1): 59– 66.

62. Pandit B, Halasi M, Gartel AL. p53 negatively regulates expression of FoxM1. Cell Cycle 2009; 8(20): 3425– 3427.

63. Barsotti AM, Prives C. Pro‑proliferative FoxM1 is a target of p53- mediated repression. Oncogene 2009; 28(48): 4295– 4305. doi: 10.1038/ onc.2009.282.

64. Wang IC, Chen YJ, Hughes D et al. Forkhead box M1 regulates the transcriptional network of genes essential for mitotic progression and genes encoding the SCF (Skp2- Cks1) ubiquitin ligase. Mol Cell Biol 2005; 25(24): 10875– 10894.

65. Fu Z, Malureanu L, Huang J et al. Plk1‑ dependent phosphorylation of FoxM1 regulates a transcriptional programme required for mitotic progression. Nat Cell Biol 2008; 10(9): 1076– 1082. doi: 10.1038/ ncb1767.

66. McKenzie L, King S, Marcar L et al. p53- dependent repression of polo‑like kinase‑ 1 (PLK1). Cell Cycle 2010; 9(20): 4200– 4212.

67. Ando K, Ozaki T, Yamamoto H et al. Polo‑like kinase 1 (Plk1) inhibits p53 function by physical interaction and phosphorylation. J Biol Chem 2004; 279(24): 25549– 25561.

68. Kruse JP, Gu W. Modes of p53 regulation. Cell 2009; 137(4): 609– 622. doi: 10.1016/ j.cell.2009.04.050.

69. Dias SS, Hogan C, Ochocka AM et al. Polo‑like kinase‑ 1 phosphorylates MDM2 at Ser260 and stimulates MDM2- mediated p53 turnover. FEBS Lett 2009; 583(22): 3543– 3548. doi: 10.1016/ j.febslet.2009.09.057.

70. Yang X, Li H, Zhou Z et al. Plk1‑ mediated phosphorylation of topors regulates p53 stability. J Biol Chem 2009; 284(28): 18588– 18592. doi: 10.1074/ jbc.C109.001560.

71. Liu XS, Li H, Song B et al. Polo‑like kinase 1 phosphorylation of G2 and S‑ phase‑ expressed 1 protein is essential for p53 inactivation during G2 checkpoint recovery. EMBO Rep 2010; 11(8): 626– 632. doi: 10.1038/ embor.2010.90.

72. Guan R, Tapang P, Leverson JD et al. Small interfering RNA‑ mediated polo‑like kinase 1 depletion preferentially reduces the survival of p53- defective, oncogenic transformed cells and inhibits tumor growth in animals. Cancer Res 2005; 65(7): 2698– 2704.

73. Lansing TJ, McConnell RT, Duckett DR et al. In vitro bio­logical activity of a novel small‑molecule inhibitor of polo‑like kinase 1. Mol Cancer Ther 2007; 6(2): 450– 459.

74. Spänkuch‑ Schmitt B, Bereiter‑ Hahn J, Kaufmann M et al. Effect of RNA silencing of polo‑like kinase‑ 1 (PLK1) on apoptosis and spindle formation in human cancer cells. J Natl Cancer Inst 2002; 94(24): 1863– 1877.

75. Raab M, Kappel S, Krämer A et al. Toxicity modelling of Plk1‑ targeted therapies in genetically engineered mice and cultured primary mammalian cells. Nat Commun 2011; 2: 395. doi: 10.1038/ ncomms1395.

76. Sur S, Pagliarini R, Bunz F et al. A panel of isogenic human cancer cells suggests a therapeutic approach for cancers with inactivated p53. Proc Natl Acad Sci U S A 2009; 106(10): 3964– 3969. doi: 10.1073/ pnas.0813333106.

77. Degenhardt Y, Greshock J, Laquerre S et al. Sensitivity of cancer cells to Plk1 inhibitor GSK461364A is associated with loss of p53 function and chromosome instability. Mol Cancer Ther 2010; 9(7): 2079– 2089. doi: 10.1158/ 1535‑ 7163.MCT‑ 10‑ 0095.

78. Yuan J, Sanhaji M, Krämer A et al. Polo‑ box domain inhibitor poloxin activates the spindle assembly checkpoint and inhibits tumor growth in vivo. Am J Pathol 2011; 179(4): 2091– 2099. doi: 10.1016/ j.ajpath.2011.06.031.

79. Steegmaier M, Hoffmann M, Baum A et al. BI 2536, a potent and selective inhibitor of polo‑like kinase 1, inhibits tumor growth in vivo. Curr Biol 2007; 17(4): 316– 322.

80. Watanabe N, Sekine T, Takagi M et al. Deficiency in chromosome congression by the inhibition of Plk1 polo box domain‑dependent recognition. J Biol Chem 2009; 284(4): 2344– 2353. doi: 10.1074/ jbc.M805308200.

81. Lu B, Mahmud H, Maass AH et al. The Plk1 inhibitor BI 2536 temporarily arrests primary cardiac fibroblasts in mitosis and generates aneuploidy in vitro. PloS One 2010; 5(9): e12963. doi: 10.1371/ journal.pone.0012963.

82. Mross K, Dittrich C, Aulitzky WE et al. A randomised phase II trial of the Polo‑like kinase inhibitor BI 2536 in chemo‑ naïve patients with unresectable exocrine adenocarcinoma of the pancreas –  a study within the Central European Society Anticancer Drug Research (CESAR) collaborative network. Br J Cancer 2012; 107(2): 280– 286. doi: 10.1038/ bjc.2012.257.

83. Sebastian M, Reck M, Waller CF et al. The efficacy and safety of BI 2536, a novel Plk‑ 1 inhibitor, in patients with stage IIIB/ IV non‑small cell lung cancer who had relapsed after, or failed, chemotherapy: results from an open‑ label, randomized phase II clinical trial. J Thorac Oncol 2010; 5(7): 1060– 1067. doi: 10.1097/ JTO.0b013e3181d95dd4.

84. Frost A, Mross K, Steinbild S et al. Phase i study of the Plk1 inhibitor BI 2536 administered intravenously on three consecutive days in advanced solid tumours. Curr Oncol 2012; 19(1): e28– e35. doi: 10.3747/ co.19.866.

85. Sanhaji M, Kreis NN, Zimmer B et al. p53 is not directly relevant to the response of polo‑like kinase 1 inhibitors. Cell Cycle 2012; 11(3): 543– 553. doi: 10.4161/ cc.11.3.19076.

86. Sanhaji M, Louwen F, Zimmer B et al. Polo‑like kinase 1inhibitors, mitotic stress and the tumor suppressor p53. Cell Cycle 2013; 12(9): 1340– 1351. doi: 10.4161/ cc.24573.

87. Khan SH, Wahl GM. p53 and pRb prevent rereplication in response to microtubule inhibitors by mediating a reversible G1 arrest. Cancer Res 1998; 58(3): 396– 401.

88. Stewart ZA, Mays D, Pietenpol JA. Defective G1- S cell cycle checkpoint function sensitizes cells to microtubule inhibitor‑induced apoptosis. Cancer Res 1999; 59(15): 3831– 3837.

89. Louwen F, Yuan J. Battle of the eternal rivals: restoring functional p53 and inhibiting polo‑like kinase 1 as cancer therapy. Oncotarget 2013; 4(7): 958– 971.

90. Kappel S, Matthess Y, Kaufmann M et al. Silencing of mammalian genes by tetracycline‑ inducible shRNA expression. Nat Protoc 2007; 2(12): 3257– 3269.

91. Matthess Y, Kappel S, Spänkuch B et al. Conditional inhibition of cancer cell proliferation by tetracycline‑ responsive, H1 promoter‑driven silencing of PLK1. Oncogene 2005; 24(18): 2973– 2980.

92. Lane HA, Nigg EA. Antibody microinjection reveals an essential role for human polo‑like kinase 1 (Plk1) in the functional maturation of mitotic centrosomes. J Cell Biol 1996; 135(6 Pt 2): 1701– 1713.

93. Cogswell JP, Brown CE, Bisi JE et al. Dominant‑ negative polo‑like kinase 1 induces mitotic catastrophe independent of cdc25C function. Cell Growth Differ 2000; 11(12): 615– 623.

94. Spänkuch‑ Schmitt B, Wolf G, Solbach C et al. Downregulation of human polo‑like kinase activity by antisense oligonucleotides induces growth inhibition in cancer cells. Oncogene 2002; 21(20): 3162– 3171.

95. Yuan J, Krämer A, Eckerdt F et al. Efficient internalization of the polo‑ box of polo‑like kinase 1 fused to an Antennapedia peptide results in inhibition of cancer cell proliferation. Cancer Res 2002; 62(15): 4186– 4190.

96. Spänkuch B, Matthess Y, Knecht R et al. Cancer inhibition in nude mice after systemic application of U6 promoter‑driven short hairpin RNAs against PLK1. J Natl Cancer Inst 2004; 96(11): 862– 872.

97. Kappel S, Matthess Y, Zimmer B et al. Tumor inhibition by genomically integrated inducible RNAi‑ cassettes. Nucleic Acids Res 2006; 34(16): 4527– 4536.

98. Lénárt P, Petronczki M, Steegmaier M et al. The small‑molecule inhibitor BI 2536 reveals novel insights into mitotic roles of polo‑like kinase 1. Curr Biol 2007; 17(4): 304– 315.

99. Hofheinz RD, Al‑ Batran SE, Hochhaus A et al. An open‑ label, phase I study of the polo‑like kinase‑ 1 inhibitor, BI 2536, in patients with advanced solid tumors. Clin Cancer 2010; 16(18): 4666– 4674. doi: 10.1158/ 1078‑ 0432.CCR‑ 10‑ 0318.

100. Mross K, Frost A, Steinbild S et al. Phase I dose escalation and pharmacokinetic study of BI 2536, a novel polo‑like kinase 1 inhibitor, in patients with advanced solid tumors. J Clin Oncol 2008; 26(34): 5511– 5517. doi: 10.1200/ JCO.2008.16.1547.

101. Schöffski P, Blay JY, De Greve J et al. Multicentric parallel phase II trial of the polo‑like kinase 1 inhibitor BI 2536 in patients with advanced head and neck cancer, breast cancer, ovarian cancer, soft tissue sarcoma and melanoma. The first protocol of the European Organization for Research and Treatment of Cancer (EORTC) Net­work Of Core Institutes (NOCI). Eur J Cancer 2010; 46(12): 2206– 2215. doi: 10.1016/ j.ejca.2010.03.039.

102. Rudolph D, Steegmaier M, Hoffmann M et al. BI 6727, a polo‑like kinase inhibitor with improved pharmacokinetic profile and broad antitumor activity. Clin Cancer Res Off J Am Assoc Cancer Res 2009; 15(9): 3094– 3102. doi: 10.1158/ 1078‑ 0432.CCR‑ 08‑ 2445.

103. Maertens J, Lubbert M, Fiedler W et al. Phase I/ II study of volasertib (BI 6727), an intravenous polo‑like kinase (Plk) inhibitor, in patients with acute myeloid leukemia (AML): results from the randomized phase II part for volasertib in combination with low‑dose cytarabine (LDAC) versus LDAC monotherapy in patients with previously untreated AML ineligible for intensive treatment. Blood (ASH Annu Meet Abstr) 2012; 120(21): abstr. 411.

104. Stadler WM, Vaughn DJ, Sonpavde G et al. An open‑ label, single‑arm, phase 2 trial of the polo‑like kinase inhibitor volasertib (BI 6727) in patients with local­­ly advanced or metastatic urothelial cancer. Cancer 2014; 120(7): 976– 982. doi: 10.1002/ cncr.28519.

105. ClinicalTrials.gov [homepage on the Internet]. A service of the U.S. National Institutes of Health; c2000– 15 [updated 2015 March 8; cited 2015 April 15]. Available from: https:/ / clinicaltrials.gov/ ct2/ show/ study/ NCT01721876?term=NCT01721876 &rank=1.

106. Olmos D, Barker D, Sharma R et al. Phase I study of GSK461364, a specific and competitive polo‑like kinase 1 inhibitor, in patients with advanced solid malignancies. Clin Cancer Res 2011; 17(10): 3420– 3430. doi: 10.1158/ 1078‑ 0432.CCR‑ 10‑ 2946.

107. Beria I, Bossi RT, Brasca MG et al. NMS‑ P937, a 4,5- dihydro‑1H‑ pyrazolo[4,3- h]quinazoline derivative as potent and selective polo‑like kinase 1 inhibitor. Bioorg Med Chem Lett 2011; 21(10): 2969– 2974. doi: 10.1016/ j.bmcl.2011.03.054.

108. Valsasina B, Beria I, Alli C et al. NMS‑ P937, an orally available, specific small‑molecule polo‑like kinase 1 inhibitor with antitumor activity in solid and hematologic malignancies. Mol Cancer Ther 2012; 11(4): 1006– 1016. doi: 10.1158/ 1535‑ 7163.MCT‑ 11‑ 0765.

109. ClinicalTrials.gov [homepage on the Internet]. A ser­vice of the U.S. National Institutes of Health; c2000– 15 [updated 2012 September 6; cited 2015 April 15]. Available from: https:/ / clinicaltrials.gov/ ct2/ show/ NCT01014429?term=NMS‑ 1286937&rank=1.

110. Johnson EF, Stewart KD, Woods KW et al. Pharmacological and functional comparison of the polo‑like kinase family: insight into inhibitor and substrate specificity. Biochemistry 2007; 46(33): 9551– 9563.

111. Elia AE, Cantley LC, Yaffe MB. Proteomic screen finds pSer/ pThr‑binding domain localizing Plk1 to mitotic substrates. Science 2003; 299(5610): 1228– 1231.

112. Elia AEH, Rellos P, Haire LF et al. The molecular basis for phosphodependent substrate targeting and regulation of Plks by the Polo‑ box domain. Cell 2003; 115(1): 83– 95.

113. Reindl W, Yuan J, Krämer A et al. Inhibition of polo‑like kinase 1 by blocking polo‑ box domain‑dependent protein‑protein interactions. Chem Biol 2008; 15(5): 459– 466. doi: 10.1016/ j.chembio­l.2008.03.013.

114. Gali‑ Muhtasib H, Roessner A, Schneider‑ Stock R. Thymoquinone: a promising anti‑cancer drug from natural sources. Int J Biochem Cell Biol 2006; 38(8): 1249– 1253.

115. Kaseb AO, Chinnakannu K, Chen D et al. Androgen receptor and E2F‑ 1 targeted thymoquinone therapy for hormone‑ refractory prostate cancer. Cancer Res 2007; 67(16): 7782– 7788.

116. Craig SN, Wyatt MD, McInnes C. Current asses­s­­-ment of polo‑like kinases as anti‑tumor drug targets. Expert Opin Drug Discov 2014; 9(7): 773– 789. doi: 10.1517/ 17460441.2014.918100.

117. Abou‑ Karam M, Shier WT. Inhibition of oncogene product enzyme activity as an approach to cancer chemoprevention. Tyrosine‑ specific protein kinase inhibition by purpurogallin from Quercus sp. nutgall. Phytother Res PTR 1999; 13(4): 337– 340.

118. Farnet CM, Wang B, Hansen M et al. Human immunodeficiency virus type 1 cDNA integration: new aromatic hydroxylated inhibitors and studies of the inhibition mechanism. Antimicrob Agents Chemother 1998; 42(9): 2245– 2253.

119. Inamori Y, Muro C, Sajima E et al. Biological activity of purpurogallin. Biosci Biotechnol Biochem 1997; 61(5): 890– 892.

120. Yun SM, Moulaei T, Lim D et al. Structural and functional analyses of minimal phosphopeptides targeting the polo‑ box domain of polo‑like kinase 1. Nat Struct Mol Biol 2009; 16(8): 876– 882. doi: 10.1038/ nsmb.1628.

121. McInnes C, Estes K, Baxter M et al. Targeting subcellular localization through the polo‑ box domain: non‑ATP competitive inhibitors recapitulate a PLK1 phenotype. Mol Cancer Ther 2012; 11(8): 1683– 1692. doi: 10.1158/ 1535‑ 7163.MCT‑ 12‑ 0006‑ T.

122. Strebhardt K, Becker S, Matthess Y. Thoughts on the current assessment of polo‑like kinase inhibitor drug discovery. Expert Opin Drug Discov 2015; 10(1): 1– 8. doi: 10.1517/ 17460441.2015.962510.

123. Strebhardt K. Multifaceted polo‑like kinases: drug targets and antitargets for cancer therapy. Nat Rev Drug Discov 2010; 9(8): 643– 660. doi: 10.1038/ nrd3184.

124. Park JE, Li L, Park J et al. Direct quantification of polo‑like kinase 1 activity in cells and tissues using a highly sensitive and specific ELISA assay. Proc Natl Acad Sci U S A 2009; 106(6): 1725– 1730. doi: 10.1073/pnas.0812135106.

Paediatric clinical oncology Surgery Clinical oncology
Forgotten password

Don‘t have an account?  Create new account

Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.


Don‘t have an account?  Create new account