Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
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
_version_ 1783422582544924672
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
work_keys_str_mv AT suriamreena evaluationofproteinkinaseinhibitorswithplk4crossoverpotentialinapreclinicalmodelofcancer
AT baileyandersw evaluationofproteinkinaseinhibitorswithplk4crossoverpotentialinapreclinicalmodelofcancer
AT tavaresmauriciot evaluationofproteinkinaseinhibitorswithplk4crossoverpotentialinapreclinicalmodelofcancer
AT gunosewoyohendra evaluationofproteinkinaseinhibitorswithplk4crossoverpotentialinapreclinicalmodelofcancer
AT dyerconnorp evaluationofproteinkinaseinhibitorswithplk4crossoverpotentialinapreclinicalmodelofcancer
AT grupenmacheralext evaluationofproteinkinaseinhibitorswithplk4crossoverpotentialinapreclinicalmodelofcancer
AT piperdavidr evaluationofproteinkinaseinhibitorswithplk4crossoverpotentialinapreclinicalmodelofcancer
AT hortonroberta evaluationofproteinkinaseinhibitorswithplk4crossoverpotentialinapreclinicalmodelofcancer
AT tomitatadanori evaluationofproteinkinaseinhibitorswithplk4crossoverpotentialinapreclinicalmodelofcancer
AT kozikowskialanp evaluationofproteinkinaseinhibitorswithplk4crossoverpotentialinapreclinicalmodelofcancer
AT roysaktimayeem evaluationofproteinkinaseinhibitorswithplk4crossoverpotentialinapreclinicalmodelofcancer
AT srednisimonet evaluationofproteinkinaseinhibitorswithplk4crossoverpotentialinapreclinicalmodelofcancer