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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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6540285/ https://www.ncbi.nlm.nih.gov/pubmed/31035676 http://dx.doi.org/10.3390/ijms20092112 |
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author | Suri, Amreena Bailey, Anders W. Tavares, Maurício T. Gunosewoyo, Hendra Dyer, Connor P. Grupenmacher, Alex T. Piper, David R. Horton, Robert A. Tomita, Tadanori Kozikowski, Alan P. Roy, Saktimayee M. Sredni, Simone T. |
author_facet | Suri, Amreena Bailey, Anders W. Tavares, Maurício T. Gunosewoyo, Hendra Dyer, Connor P. Grupenmacher, Alex T. Piper, David R. Horton, Robert A. Tomita, Tadanori Kozikowski, Alan P. Roy, Saktimayee M. Sredni, Simone T. |
author_sort | Suri, Amreena |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-6540285 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-65402852019-06-04 Evaluation of Protein Kinase Inhibitors with PLK4 Cross-Over Potential in a Pre-Clinical Model of Cancer Suri, Amreena Bailey, Anders W. Tavares, Maurício T. Gunosewoyo, Hendra Dyer, Connor P. Grupenmacher, Alex T. Piper, David R. Horton, Robert A. Tomita, Tadanori Kozikowski, Alan P. Roy, Saktimayee M. Sredni, Simone T. Int J Mol Sci Article 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. MDPI 2019-04-29 /pmc/articles/PMC6540285/ /pubmed/31035676 http://dx.doi.org/10.3390/ijms20092112 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Suri, Amreena Bailey, Anders W. Tavares, Maurício T. Gunosewoyo, Hendra Dyer, Connor P. Grupenmacher, Alex T. Piper, David R. Horton, Robert A. Tomita, Tadanori Kozikowski, Alan P. Roy, Saktimayee M. Sredni, Simone T. Evaluation of Protein Kinase Inhibitors with PLK4 Cross-Over Potential in a Pre-Clinical Model of Cancer |
title | 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_short | 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 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6540285/ https://www.ncbi.nlm.nih.gov/pubmed/31035676 http://dx.doi.org/10.3390/ijms20092112 |
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