Skip to main content
SpringerLink
Log in

Diversity evolution and jump of Polo-like kinase 1 inhibitors

  • Reviews
  • Special Topic Chemistry for Life Sciences
  • Published:
Science China Chemistry Aims and scope Submit manuscript

Abstract

Polo-like kinase 1 (Plk1), a member of a family of serine/threonine kinases, is an attractive target for the development of anticancer drugs because it is involved in the regulation of cell-cycle progression and cytokinesis. This kinase provides two pockets for developing Plk1 inhibitors: the N-terminal catalytic domain (NCD) and the polo-box domain (PBD). For both of the two pockets, some natural products were identified as Plk1 inhibitors and some synthetic Plk1 inhibitors were developed by mimicking ATP and phosphopeptides, natural products binding to NCD and PBD respectively. This article not only reviews the progression of Plk1 inhibitors binding to these two pockets, but also discusses diversity evolution and jump in the process of drug development using Plk1 inhibitors as examples and how they impact on drug design and pharmacophore modeling.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Gorse AD. Diversity in medicinal chemistry space. Curr Top Med Chem, 2006, 6: 3–18

    Article  CAS  Google Scholar 

  2. Xu J, Gu Q, Liu HB, Zhou JJ, Bu XZ, Huang ZS, Lu G, Li D, Wei DQ, Wang L, Gu LQ. Chemomics and drug innovation. Sci China Chem, 2013, 56: 71–85

    Article  CAS  Google Scholar 

  3. Lachance H, Wetzel S, Kumar K, Wadmann H. Charting, navigating, and populating natural product chemical space for drug discovery. J Med Chem, 2012, 55: 5989–6001

    Article  CAS  Google Scholar 

  4. Newman DJ, Cragg GM. Natural product scaffolds as leads to drugs. Future Med Chem, 2009, 1: 1415–1427

    Article  CAS  Google Scholar 

  5. Liao C, Sitzmann M, Pugliese A, Nicklaus MC. Software and resources for computational medicinal chemistry. Future Med Chem, 2011, 3: 1057–1085

    Article  CAS  Google Scholar 

  6. Cohen P. Protein kinases—the major drug targets of the twenty-first century? Nat Rev Drug Discov, 2002, 1: 309–315

    Article  CAS  Google Scholar 

  7. Liao JJ. Molecular recognition of protein kinase binding pockets for design of potent and selective kinase inhibitors. J Med Chem, 2007, 50: 409–424

    Article  CAS  Google Scholar 

  8. Ghose AK, Herbertz T, Pippin DA, Salvino JM, Mallamo JP. Knowledge based prediction of ligand binding modes and rational inhibitor design for kinase drug discovery. J Med Chem, 2008, 51: 5149–5171

    Article  CAS  Google Scholar 

  9. de Carcer G, Manning G, Malumbres M. From Plk1 to Plk5: functional evolution of polo-like kinases. Cell Cycle, 2011, 10: 2255–2262

    Article  Google Scholar 

  10. Archambault V, Glover DM. Polo-like kinases: Conservation and divergence in their functions and regulation. Nat Rev Mol Cell Biol, 2009, 10: 265–275

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  13. McInnes C, Wyatt MD. PLK1 as an oncology target: current status and future potential. Drug Discovery Today, 2011, 16: 619–625

    Article  CAS  Google Scholar 

  14. Chopra P, Sethi G, Dastidar SG, Ray A. Polo-like kinase inhibitors: an emerging opportunity for cancer therapeutics. Expert Opin Investig Drugs, 2010, 19: 27–43

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  16. Park JE, Soung NK, Johmura Y, Kang YH, Liao C, Lee KH, Park CH, Nicklaus MC, Lee KS. Polo-box domain: A versatile mediator of polo-like kinase function. Cell Mol Life Sci, 2010, 67: 1957–1970

    Article  CAS  Google Scholar 

  17. Steegmaier M, Hoffmann M, Baum A, Lenart P, Petronczki M, Krssak M, Gurtler U, Garin-Chesa P, Lieb S, Quant J, Grauert M, Adolf GR, Kraut N, Peters JM, Rettig WJ. BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo. Curr Biol, 2007, 17: 316–322

    Article  CAS  Google Scholar 

  18. Kothe M, Kohls D, Low S, Coli R, Cheng AC, Jacques SL, Johnson TL, Lewis C, Loh C, Nonomiya J, Sheils AL, Verdries KA, Wynn TA, Kuhn C, Ding YH. Structure of the catalytic domain of human polo-like kinase 1. Biochemistry, 2007, 46: 5960–5971

    Article  CAS  Google Scholar 

  19. Rudolph D, Steegmaier M, Hoffmann M, Grauert M, Baum A, Quant J, Haslinger C, Garin-Chesa P, Adolf GR. BI 6727, a Polo-like kinase inhibitor with improved pharmacokinetic profile and broad antitumor activity. Clin Cancer Res, 2009, 15: 3094–3102

    Article  CAS  Google Scholar 

  20. Olmos D, Barker D, Sharma R, Brunetto AT, Yap TA, Taegtmeyer AB, Barriuso J, Medani H, Degenhardt YY, Allred AJ, Smith DA, Murray SC, Lampkin TA, Dar MM, Wilson R, de Bono JS, Blagden SP. 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: 3420–3430

    Article  CAS  Google Scholar 

  21. Spaniol K, Boos J, Lanvers-Kaminsky C. An in-vitro evaluation of the polo-like kinase inhibitor GW843682X against paediatric malignancies. Anticancer Drugs, 2011, 22: 531–542

    Article  CAS  Google Scholar 

  22. Lansing TJ, McConnell RT, Duckett DR, Spehar GM, Knick VB, Hassler DF, Noro N, Furuta M, Emmitte KA, Gilmer TM, Mook RA, Cheung M. In vitro biological activity of a novel small-molecule inhibitor of polo-like kinase 1. Molecular Cancer Therapeutics, 2007, 6: 450–459

    Article  CAS  Google Scholar 

  23. Beria I, Bossi RT, Brasca MG, Caruso M, Ceccarelli W, Fachin G, Fasolini M, Forte B, Fiorentini F, Pesenti E, Pezzetta D, Posteri H, Scolaro A, Re Depaolini S, Valsasina B. 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: 2969–2974

    Article  CAS  Google Scholar 

  24. Casolaro A, Golay J, Albanese C, Ceruti R, Patton V, Cribioli S, Pezzoni A, Losa M, Texido G, Giussani U, Marchesi F, Amboldi N, Valsasina B, Bungaro S, Cazzaniga G, Rambaldi A, Introna M, Pesenti E, Alzani R. The Polo-Like Kinase 1 (PLK1) Inhibitor NMS-P937 Is Effective in a New Model of Disseminated Primary CD56(+) Acute Monoblastic Leukaemia. PLoS One, 2013, 8: e58424

    Article  CAS  Google Scholar 

  25. Caruso M, Valsasina B, Ballinari D, Bertrand J, Brasca MG, Caldarelli M, Cappella P, Fiorentini F, Gianellini LM, Scolaro A, Beria I. 5-(2-amino-pyrimidin-4-yl)-1H-pyrrole and 2-(2-amino-pyrimidin-4-yl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one derivatives as new classes of selective and orally available Polo-like kinase 1 inhibitors. Bioorg Med Chem Lett, 2012, 22: 96–101

    Article  CAS  Google Scholar 

  26. Kwok Leung Cheung A, Ip JC, Lung HL, Zhen Wu J, Tsao SW, Li Lung M. Polo-like kinase (PLK) inhibitor, Ro5203280, has potent anti-tumor activity in nasopharyngeal carcinoma. Mol Cancer Ther, 2013

    Google Scholar 

  27. Nie Z, Feher V, Natala S, McBride C, Kiryanov A, Jones B, Lam B, Liu Y, Kaldor S, Stafford J, Hikami K, Uchiyama N, Kawamoto T, Hikichi Y, Matsumoto S, Amano N, Zhang L, Hosfield D, Skene R, Zou H, Cao X, Ichikawa T. Discovery of TAK-960: An orally available small molecule inhibitor of polo-like kinase 1 (PLK1). Bioorg Med Chem Lett, 2013, 23: 3662–3666

    Article  CAS  Google Scholar 

  28. Hikichi Y, Honda K, Hikami K, Miyashita H, Kaieda I, Murai S, Uchiyama N, Hasegawa M, Kawamoto T, Sato T, Ichikawa T, Cao S, Nie Z, Zhang L, Yang J, Kuida K, Kupperman E. TAK-960, a novel, orally available, selective inhibitor of polo-like kinase 1, shows broad-spectrum preclinical antitumor activity in multiple dosing regimens. Mol Cancer Ther, 2012, 11: 700–709

    Article  CAS  Google Scholar 

  29. Elling RA, Fucini RV, Romanowski MJ. Structures of the wild-type and activated catalytic domains of Brachydanio rerio Polo-like kinase 1 (Plk1): changes in the active-site conformation and interactions with ligands. Acta Crystallogr D Biol Crystallogr, 2008, 64: 909–918

    Article  CAS  Google Scholar 

  30. Kothe M, Kohls D, Low S, Coli R, Rennie GR, Feru F, Kuhn C, Ding YH. Selectivity-determining residues in Plk1. Chem Biol Drug Des, 2007, 70: 540–546

    Article  CAS  Google Scholar 

  31. Toyoshima-Morimoto F, Taniguchi E, Shinya N, Iwamatsu A, Nishida E. Polo-like kinase 1 phosphorylates cyclin B1 and targets it to the nucleus during prophase. Nature, 2001, 410: 215–220

    Article  CAS  Google Scholar 

  32. Duffey MO, Vos TJ, Adams R, Alley J, Anthony J, Barrett C, Bharathan I, Bowman D, Bump NJ, Chau R, Cullis C, Driscoll DL, Elder A, Forsyth N, Frazer J, Guo J, Guo L, Hyer ML, Janowick D, Kulkarni B, Lai SJ, Lasky K, Li G, Li J, Liao D, Little J, Peng B, Qian MG, Reynolds DJ, Rezaei M, Scott MP, Sells TB, Shinde V, Shi QJ, Sintchak MD, Soucy F, Sprott KT, Stroud SG, Nestor M, Visiers I, Weatherhead G, Ye Y, D’Amore N. Discovery of a potent and orally bioavailable benzolactam-derived inhibitor of Polo-like kinase 1 (MLN0905). J Med Chem, 2012, 55: 197–208

    Article  CAS  Google Scholar 

  33. Keppner S, Proschak E, Schneider G, Spankuch B. Identification and validation of a potent type II inhibitor of inactive polo-like kinase 1. ChemMedChem, 2009, 4: 1806–1809

    Article  CAS  Google Scholar 

  34. Uckun FM, Dibirdik I, Qazi S, Vassilev A, Ma H, Mao C, Benyumov A, Emami KH. Anti-breast cancer activity of LFM-A13, a potent inhibitor of Polo-like kinase (PLK). Bioorg Med Chem, 2007, 15: 800–814

    Article  CAS  Google Scholar 

  35. Elia AE, Rellos P, Haire LF, Chao JW, Ivins FJ, Hoepker K, Mohammad D, Cantley LC, Smerdon SJ, Yaffe MB. The molecular basis for phosphodependent substrate targeting and regulation of Plks by the Polo-box domain. Cell, 2003, 115: 83–95

    Article  CAS  Google Scholar 

  36. Kang YH, Park JE, Yu LR, Soung NK, Yun SM, Bang JK, Seong YS, Yu H, Garfield S, Veenstra TD, Lee KS. Self-regulated Plk1 recruitment to kinetochores by the Plk1-PBIP1 interaction is critical for proper chromosome segregation. Mol Cell, 2006, 24: 409–422

    Article  CAS  Google Scholar 

  37. Yun SM, Moulaei T, Lim D, Bang JK, Park JE, Shenoy SR, Liu F, Kang YH, Liao C, Soung NK, Lee S, Yoon DY, Lim Y, Lee DH, Otaka A, Appella E, McMahon JB, Nicklaus MC, Burke TR Jr, Yaffe MB, Wlodawer A, Lee KS. Structural and functional analyses of minimal phosphopeptides targeting the polo-box domain of polo-like kinase 1. Nat Struct Mol Biol, 2009, 16: 876–882

    Article  CAS  Google Scholar 

  38. Huggins DJ, McKenzie GJ, Robinson DD, Narvaez AJ, Hardwick B, Roberts-Thomson M, Venkitaraman AR, Grant GH, Payne MC. Computational analysis of phosphopeptide binding to the polo-box domain of the mitotic kinase PLK1 using molecular dynamics simulation. PLoS Comput Biol, 2010, 6

  39. Liu F, Park JE, Qian WJ, Lim D, Graber M, Berg T, Yaffe MB, Lee KS, Burke TR Jr. Serendipitous alkylation of a Plk1 ligand uncovers a new binding channel. Nat Chem Biol, 2011, 7: 595–601

    Article  CAS  Google Scholar 

  40. Liu F, Park JE, Qian WJ, Lim D, Scharow A, Berg T, Yaffe MB, Lee KS, Burke TR Jr. Identification of high affinity polo-like kinase 1 (Plk1) polo-box domain binding peptides using oxime-based diversification. ACS Chem Biol, 2012, 7: 805–810

    Article  CAS  Google Scholar 

  41. Murugan RN, Park JE, Lim D, Ahn M, Cheong C, Kwon T, Nam KY, Choi SH, Kim BY, Yoon DY, Yaffe MB, Yu DY, Lee KS, Bang JK. Development of cyclic peptomer inhibitors targeting the polo-box domain of polo-like kinase 1. Bioorg Med Chem, 2013, 21: 2623–2634

    Article  CAS  Google Scholar 

  42. Yin Z, Song Y, Rehse PH. Thymoquinone blocks pSer/pThr recognition by Plk1 Polo-box domain as a phosphate mimic. ACS Chem Biol, 2013, 8: 303–308

    Article  CAS  Google Scholar 

  43. Reindl W, Yuan J, Kramer A, Strebhardt K, Berg T. Inhibition of polo-like kinase 1 by blocking polo-box domain-dependent protein-protein interactions. Chem Biol, 2008, 15: 459–466

    Article  CAS  Google Scholar 

  44. Liao C, Park J-E, Bang JK, Nicklaus MC, Lee KS. Probing Binding Modes of Small Molecule Inhibitors to the Polo-Box Domain of Human Polo-like Kinase 1. ACS Med Chem Lett, 2010, 1: 110–114

    Article  CAS  Google Scholar 

  45. Reindl W, Yuan J, Kramer A, Strebhardt K, Berg T. A pan-specific inhibitor of the polo-box domains of polo-like kinases arrests cancer cells in mitosis. Chembiochem, 2009, 10: 1145–1148

    Article  CAS  Google Scholar 

  46. Watanabe N, Sekine T, Takagi M, Iwasaki J, Imamoto N, Kawasaki H, Osada H. Deficiency in chromosome congression by the inhibition of Plk1 polo box domain-dependent recognition. J Biol Chem, 2009, 284: 2344–2353

    Article  CAS  Google Scholar 

  47. Gumireddy K, Reddy MV, Cosenza SC, Boominathan R, Baker SJ, Papathi N, Jiang J, Holland J, Reddy EP. ON01910, a non-ATP-competitive small molecule inhibitor of Plk1, is a potent anticancer agent. Cancer Cell, 2005, 7: 275–286

    Article  CAS  Google Scholar 

  48. Tanaka H, Ohshima N, Ikenoya M, Komori K, Katoh F, Hidaka H. HMN-176, an active metabolite of the synthetic antitumor agent HMN-214, restores chemosensitivity to multidrug-resistant cells by targeting the transcription factor NF-Y. Cancer Res, 2003, 63: 6942–6947

    CAS  Google Scholar 

  49. Lu J, Xin S, Meng H, Veldman M, Schoenfeld D, Che C, Yan R, Zhong H, Li S, Lin S. A Novel Anti-Tumor Inhibitor Identified by Virtual Screen with PLK1 Structure and Zebrafish Assay. PLoS One, 2013, 8: e53317

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Medical Engineering, Hefei University of Technology, Hefei, 230009, China

    Chenzhong Liao & RiSheng Yao

Authors
  1. Chenzhong Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. RiSheng Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chenzhong Liao.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liao, C., Yao, R. Diversity evolution and jump of Polo-like kinase 1 inhibitors. Sci. China Chem. 56, 1392–1401 (2013). https://doi.org/10.1007/s11426-013-4963-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11426-013-4963-0

Keywords

Search

Navigation