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

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...

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Main Authors: 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
Format: Article
Language:English
Published: MDPI AG 2019-04-01
Series:International Journal of Molecular Sciences
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Online Access:https://www.mdpi.com/1422-0067/20/9/2112
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spelling doaj-aa0a2fae070a4cd0977b4011fb4583712020-11-25T01:19:21ZengMDPI AGInternational Journal of Molecular Sciences1422-00672019-04-01209211210.3390/ijms20092112ijms20092112Evaluation of Protein Kinase Inhibitors with PLK4 Cross-Over Potential in a Pre-Clinical Model of CancerAmreena Suri0Anders W. Bailey1Maurício T. Tavares2Hendra Gunosewoyo3Connor P. Dyer4Alex T. Grupenmacher5David R. Piper6Robert A. Horton7Tadanori Tomita8Alan P. Kozikowski9Saktimayee M. Roy10Simone T. Sredni11Division of Pediatric Neurosurgery, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611, USADivision of Pediatric Neurosurgery, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611, USADepartment of Pharmacy, University of São Paulo, São Paulo, SP 05508-900, BrazilSchool of Pharmacy and Biomedical Sciences, Curtin University, Bentley, Perth, WA 6102, AustraliaDivision of Pediatric Neurosurgery, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611, USADepartment of Ophtalmology, Universidade Federal de São Paulo, São Paulo, SP 04023-062, BrazilThermo Fisher Scientific, Research and Development, Biosciences Division, Carlsbad, CA 92008, USAThermo Fisher Scientific, Research and Development, Biosciences Division, Carlsbad, CA 92008, USADivision of Pediatric Neurosurgery, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611, USAStar Wise Therapeutics, Madison, WI 53719, USADepartment of Pharmacology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USADivision of Pediatric Neurosurgery, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611, USAPolo-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.https://www.mdpi.com/1422-0067/20/9/2112CFI-400945CFI-400437R1530centrinoneaxitinibKW-2449alisertibAURKrhabdoid tumorAT/RTmedulloblastomaprotein kinasebrain exposure
collection DOAJ
language English
format Article
sources DOAJ
author 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
spellingShingle 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
Evaluation of Protein Kinase Inhibitors with PLK4 Cross-Over Potential in a Pre-Clinical Model of Cancer
International Journal of Molecular Sciences
CFI-400945
CFI-400437
R1530
centrinone
axitinib
KW-2449
alisertib
AURK
rhabdoid tumor
AT/RT
medulloblastoma
protein kinase
brain exposure
author_facet 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
author_sort Amreena Suri
title Evaluation of Protein Kinase Inhibitors with PLK4 Cross-Over Potential in a Pre-Clinical Model of Cancer
title_short Evaluation of Protein Kinase Inhibitors with PLK4 Cross-Over Potential in a Pre-Clinical Model of Cancer
title_full Evaluation of Protein Kinase Inhibitors with PLK4 Cross-Over Potential in a Pre-Clinical Model of Cancer
title_fullStr Evaluation of Protein Kinase Inhibitors with PLK4 Cross-Over Potential in a Pre-Clinical Model of Cancer
title_full_unstemmed Evaluation of Protein Kinase Inhibitors with PLK4 Cross-Over Potential in a Pre-Clinical Model of Cancer
title_sort evaluation of protein kinase inhibitors with plk4 cross-over potential in a pre-clinical model of cancer
publisher MDPI AG
series International Journal of Molecular Sciences
issn 1422-0067
publishDate 2019-04-01
description 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.
topic CFI-400945
CFI-400437
R1530
centrinone
axitinib
KW-2449
alisertib
AURK
rhabdoid tumor
AT/RT
medulloblastoma
protein kinase
brain exposure
url https://www.mdpi.com/1422-0067/20/9/2112
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