Evaluation of protein kinase inhibitors with plk4 cross-over potential in a pre-clinical model of cancer

Amreena Suri, Anders W. Bailey, Maurício T. Tavares, Hendra Gunosewoyo, Connor P. Dyer, Alex T. Grupenmacher, David R. Piper, Robert A. Horton, Tadanori Tomita, Alan P. Kozikowski, Saktimayee M. Roy, Simone Trieger Sredni*

*Corresponding author for this work

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Polo-like kinase 4 (PLK4) is a cell cycle-regulated protein kinase (PK) recruited at the centrosome in dividing cells. Its overexpression triggers centrosome amplification, which is associated with genetic instability and carcinogenesis. In previous work, we established that PLK4 is overexpressed in pediatric embryonal brain tumors (EBT). We also demonstrated that PLK4 inhibition exerted a cytostatic effect in EBT cells. Here, we examined an array of PK inhibitors (CFI-400945, CFI-400437, centrinone, centrinone-B, R-1530, axitinib, KW-2449, and alisertib) for their potential crossover to PLK4 by comparative structural docking and activity inhibition in multiple established embryonal tumor cell lines (MON, BT-12, BT-16, DAOY, D283). Our analyses demonstrated that: (1) CFI-400437 had the greatest impact overall, but similar to CFI-400945, it is not optimal for brain exposure. Also, their phenotypic anti-cancer impact may, in part, be a consequence of the inhibition of Aurora kinases (AURKs). (2) Centrinone and centrinone B are the most selective PLK4 inhibitors but they are the least likely to penetrate the brain. (3) KW-2449, R-1530 and axitinib are the ones predicted to have moderate-to-good brain penetration. In conclusion, a new selective PLK4 inhibitor with favorable physiochemical properties for optimal brain exposure can be beneficial for the treatment of EBT.

Original languageEnglish (US)
Article number2112
JournalInternational journal of molecular sciences
Volume20
Issue number9
DOIs
StatePublished - May 1 2019

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Keywords

  • Alisertib
  • At/rt
  • Aurk
  • Axitinib
  • Brain exposure
  • Centrinone
  • Cfi-400437
  • Cfi-400945
  • Kw-2449
  • Medulloblastoma
  • Protein kinase
  • R1530
  • Rhabdoid tumor

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Cite this

Suri, A., Bailey, A. W., Tavares, M. T., Gunosewoyo, H., Dyer, C. P., Grupenmacher, A. T., Piper, D. R., Horton, R. A., Tomita, T., Kozikowski, A. P., Roy, S. M., & Sredni, S. T. (2019). Evaluation of protein kinase inhibitors with plk4 cross-over potential in a pre-clinical model of cancer. International journal of molecular sciences, 20(9), [2112]. https://doi.org/10.3390/ijms20092112