A selective inhibitor of the Polo-box domain of Polo-like kinase 1 identified by virtual screening

Publication type:
Journal article
Metadata:
Autoren
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000460683800014&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1016/j.jare.2018.10.002
eISSN
2090-1224
Externe Identifier
  • Clarivate Analytics Document Solution ID: HO1QC
  • PubMed Identifier: 30899597
ISSN
2090-1232
Zeitschrift
JOURNAL OF ADVANCED RESEARCH
Schlüsselwörter
  • Cell cycle
  • Natural products
  • Neoplasms
  • PyRx
  • Targeted chemotherapy
  • Virtual drug screening
Paginierung
145 - 156
Datum der Veröffentlichung
2019
Status
Published
Titel
A selective inhibitor of the Polo-box domain of Polo-like kinase 1 identified by virtual screening
Sub types
  • Article
Ausgabe der Zeitschrift
16

Data source: Web of Science (Lite)

Other metadata sources:
Autoren
DOI
10.1016/j.jare.2018.10.002
ISSN
2090-1232
Zeitschrift
Journal of Advanced Research
Sprache
en
Paginierung
145 - 156
Datum der Veröffentlichung
2019
Status
Published
Herausgeber
Elsevier BV
Herausgeber URL
http://dx.doi.org/10.1016/j.jare.2018.10.002
Datum der Datenerfassung
2022
Titel
A selective inhibitor of the Polo-box domain of Polo-like kinase 1 identified by virtual screening
Ausgabe der Zeitschrift
16

Data source: Crossref

Abstract
Polo-like kinase 1 (PLK1), a member of the Polo-like kinase family, plays an important regulatory role in mitosis and cell cycle progression. PLK1 overexpression is correlated with tumourigenesis and poor prognosis in cancer patients. Therefore, the identification of novel compounds that inhibit PLK1 would provide attractive therapeutic approaches. Although some PLK1 kinase inhibitors have been developed, their application has been limited by off-target effects. PLK1 contains a regulatory domain named the Polo-box domain (PBD), which is characteristic only for the Polo-like kinase family. This domain represents an alternative therapeutic target with higher selectivity for PLK1. In this study, we applied <i>in silico</i> virtual drug screening, fluorescence polarization and microscale thermophoresis to identify new scaffolds targeting the PBD of PLK1. One compound, 3-{[(1R,9S)-3-(naphthalen-2-yl)-6-oxo-7,11-diazatricyclo[7.3.1.0<sup>2</sup>,<sup>7</sup>]trideca-2,4-dien-11-yl]methyl}benzonitrile (designated compound <b>(1)</b>), out of a total of 30,793 natural product derivatives, inhibited the PLK1 PBD with high selectivity (IC50: 17.9 ± 0.5 µM). This compound inhibited the growth of cultured leukaemia cells (CCRF-CEM and CEM/ADR5000) and arrested the cell cycle in the G2/M phase, which is characteristic for PLK1 inhibitors. Immunofluorescence analyses showed that treatment with compound <b>(1)</b> disrupted spindle formation due to the aberrant localization of PLK1 during the mitotic process, leading to G2/M arrest and ultimately cell death. In conclusion, compound <b>(1)</b> is a selective PLK1 inhibitor that inhibits cancer cell growth. It represents a chemical scaffold for the future synthesis of new selective PLK1 inhibitors for cancer therapy.
Addresses
  • Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz 55128, Germany.
Autoren
DOI
10.1016/j.jare.2018.10.002
eISSN
2090-1224
Externe Identifier
  • PubMed Identifier: 30899597
  • PubMed Central ID: PMC6412170
Funding acknowledgements
  • Institute of Molecular Biology Core Facility:
  • German Academic Exchange Service (DAAD):
  • Deutsche Forschungsgemeinschaft: INST 268/281-1 FUGG
Open access
true
ISSN
2090-1232
Zeitschrift
Journal of advanced research
Sprache
eng
Medium
Electronic-eCollection
Online publication date
2018
Open access status
Open Access
Paginierung
145 - 156
Datum der Veröffentlichung
2019
Status
Published
Publisher licence
CC BY-NC-ND
Datum der Datenerfassung
2019
Titel
A selective inhibitor of the Polo-box domain of Polo-like kinase 1 identified by virtual screening.
Sub types
  • research-article
  • Journal Article
Ausgabe der Zeitschrift
16

Files

https://europepmc.org/articles/PMC6412170?pdf=render

Data source: Europe PubMed Central

Abstract
Polo-like kinase 1 (PLK1), a member of the Polo-like kinase family, plays an important regulatory role in mitosis and cell cycle progression. PLK1 overexpression is correlated with tumourigenesis and poor prognosis in cancer patients. Therefore, the identification of novel compounds that inhibit PLK1 would provide attractive therapeutic approaches. Although some PLK1 kinase inhibitors have been developed, their application has been limited by off-target effects. PLK1 contains a regulatory domain named the Polo-box domain (PBD), which is characteristic only for the Polo-like kinase family. This domain represents an alternative therapeutic target with higher selectivity for PLK1. In this study, we applied in silico virtual drug screening, fluorescence polarization and microscale thermophoresis to identify new scaffolds targeting the PBD of PLK1. One compound, 3-{[(1R,9S)-3-(naphthalen-2-yl)-6-oxo-7,11-diazatricyclo[7.3.1.02,7]trideca-2,4-dien-11-yl]methyl}benzonitrile (designated compound (1)), out of a total of 30,793 natural product derivatives, inhibited the PLK1 PBD with high selectivity (IC50: 17.9 ± 0.5 µM). This compound inhibited the growth of cultured leukaemia cells (CCRF-CEM and CEM/ADR5000) and arrested the cell cycle in the G2/M phase, which is characteristic for PLK1 inhibitors. Immunofluorescence analyses showed that treatment with compound (1) disrupted spindle formation due to the aberrant localization of PLK1 during the mitotic process, leading to G2/M arrest and ultimately cell death. In conclusion, compound (1) is a selective PLK1 inhibitor that inhibits cancer cell growth. It represents a chemical scaffold for the future synthesis of new selective PLK1 inhibitors for cancer therapy.
Date of acceptance
2018
Autoren
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/30899597
DOI
10.1016/j.jare.2018.10.002
Externe Identifier
  • PubMed Central ID: PMC6412170
ISSN
2090-1232
Zeitschrift
J Adv Res
Schlüsselwörter
  • CAMKK2, calcium/calmodulin-dependent protein kinase kinase 2
  • CDK, cyclin-dependent kinase
  • Cell cycle
  • IC50, 50% inhibition concentration
  • LK, Polo-like kinase
  • Natural products
  • Neoplasms
  • PBD, Polo-box domain
  • PC, Polo-box cap
  • PyRx
  • Targeted chemotherapy
  • Virtual drug screening
Sprache
eng
Country
Egypt
Paginierung
145 - 156
PII
S2090-1232(18)30107-3
Datum der Veröffentlichung
2019
Status
Published online
Titel
A selective inhibitor of the Polo-box domain of Polo-like kinase 1 identified by virtual screening.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
16

Data source: PubMed

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