Evaluation of Protein Kinase Inhibitors with PLK4 Cross-Over Potential in a Pre-Clinical Model of Cancer.
Animals
Cell Line, Tumor
Cell Proliferation
/ drug effects
Disease Models, Animal
Drug Evaluation, Preclinical
Enzyme Activation
Humans
Hydrophobic and Hydrophilic Interactions
Models, Molecular
Molecular Conformation
Molecular Structure
Neoplasms
/ drug therapy
Protein Binding
Protein Kinase Inhibitors
/ chemistry
Protein Serine-Threonine Kinases
/ antagonists & inhibitors
Structure-Activity Relationship
Xenograft Model Antitumor Assays
AT/RT
AURK
CFI-400437
CFI-400945
KW-2449
R1530
alisertib
axitinib
brain exposure
centrinone
medulloblastoma
protein kinase
rhabdoid tumor
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
29 Apr 2019
29 Apr 2019
Historique:
received:
06
04
2019
revised:
26
04
2019
accepted:
26
04
2019
entrez:
1
5
2019
pubmed:
1
5
2019
medline:
21
8
2019
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31035676
pii: ijms20092112
doi: 10.3390/ijms20092112
pmc: PMC6540285
pii:
doi:
Substances chimiques
Protein Kinase Inhibitors
0
PLK4 protein, human
EC 2.7.1.-
Protein Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : NCI NIH HHS
ID : P30 CA060553
Pays : United States
Organisme : Musella Foundation For Brain Tumor Research and Information
ID : 925648
Organisme : Max Cure Foundation
ID : 955928
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