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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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 |
work_keys_str_mv |
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