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Evaluation of Protein Kinase Inhibitors with PLK4 Cross-Over Potential in a Pre-Clinical Model of Cancer

1
Division of Pediatric Neurosurgery, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611, USA
2
Cancer Biology and Epigenomics Program, Stanley Manne Children’s Research Institute, Chicago, IL 60614, USA
3
Department of Pharmacy, University of São Paulo, São Paulo, SP 05508-900, Brazil
4
School of Pharmacy and Biomedical Sciences, Curtin University, Bentley, Perth, WA 6102, Australia
5
Department of Ophtalmology, Universidade Federal de São Paulo, São Paulo, SP 04023-062, Brazil
6
Thermo Fisher Scientific, Research and Development, Biosciences Division, Carlsbad, CA 92008, USA
7
Department of Surgery, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA
8
Star Wise Therapeutics, Madison, WI 53719, USA
9
Department of Pharmacology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally.
Int. J. Mol. Sci. 2019, 20(9), 2112; https://doi.org/10.3390/ijms20092112
Received: 6 April 2019 / Revised: 26 April 2019 / Accepted: 26 April 2019 / Published: 29 April 2019
(This article belongs to the Special Issue Kinase Signal Transduction 2019)
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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. View Full-Text
Keywords: CFI-400945; CFI-400437; R1530; centrinone; axitinib; KW-2449; alisertib; AURK; rhabdoid tumor; AT/RT; medulloblastoma; protein kinase; brain exposure CFI-400945; CFI-400437; R1530; centrinone; axitinib; KW-2449; alisertib; AURK; rhabdoid tumor; AT/RT; medulloblastoma; protein kinase; brain exposure
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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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. Evaluation of Protein Kinase Inhibitors with PLK4 Cross-Over Potential in a Pre-Clinical Model of Cancer. Int. J. Mol. Sci. 2019, 20, 2112.

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