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 T. Sredni

doi:10.3390/ijms20092112

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 T. Sredni^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

32 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 language	English (US)
Article number	2112
Journal	International journal of molecular sciences
Volume	20
Issue number	9
DOIs	https://doi.org/10.3390/ijms20092112
State	Published - May 1 2019

Funding

Funding: This research was supported by the Musella Foundation for Brain Cancer Research and Information and the Max Cure Foundation. Acknowledgments: We thank Daniel Martin Watterson for his guidance and careful review of the manuscript, Oluseye Onajole for his valuable suggestions, Andrew Shiau and Mehmet Kahraman, Small Molecule Discovery Program, Ludwig Institute for Cancer Research for providing centrinone and centrinone B, Jessica Jakubowski and Jacques Sredni for editorial assistance, and Paul Mehl at the Northwestern University Flow Cytometry Core Facility, which is supported by Cancer Center Support Grant - NCI CA060553. We thank Daniel MartinWatterson for his guidance and careful review of the manuscript, Oluseye Onajole for his valuable suggestions, Andrew Shiau and Mehmet Kahraman, Small Molecule Discovery Program, Ludwig Institute for Cancer Research for providing centrinone and centrinone B, Jessica Jakubowski and Jacques Sredni for editorial assistance, and Paul Mehl at the Northwestern University Flow Cytometry Core Facility, which is supported by Cancer Center Support Grant - NCI CA060553.

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

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3390/ijms20092112

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), Article 2112. https://doi.org/10.3390/ijms20092112

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

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.",

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AU - Suri, Amreena

AU - Bailey, Anders W.

AU - Tavares, Maurício T.

AU - Gunosewoyo, Hendra

AU - Dyer, Connor P.

AU - Grupenmacher, Alex T.

AU - Piper, David R.

AU - Horton, Robert A.

AU - Tomita, Tadanori

AU - Kozikowski, Alan P.

AU - Roy, Saktimayee M.

AU - Sredni, Simone T.

PY - 2019/5/1

Y1 - 2019/5/1

N2 - 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.

AB - 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.

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KW - Cfi-400945

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KW - Protein kinase

KW - R1530

KW - Rhabdoid tumor

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DO - 10.3390/ijms20092112

M3 - Article

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VL - 20

JO - International journal of molecular sciences

JF - International journal of molecular sciences

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ER -

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

Abstract

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Keywords

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UN SDGs

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