Identification of inhibitors of the polo-box domain of polo-like kinase 1 from natural and semisynthetic compounds
- Publication type:
- Journal article
- Metadata:
-
- Autoren
- Sara Abdelfatah
- Edmond Fleischer
- Anette Klinger
- Vincent Kam Wai Wong
- Thomas Efferth
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000512107200001&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.1007/s10637-019-00752-0
- eISSN
- 1573-0646
- Externe Identifier
- Clarivate Analytics Document Solution ID: KJ5NL
- PubMed Identifier: 30877426
- ISSN
- 0167-6997
- Ausgabe der Veröffentlichung
- 1
- Zeitschrift
- INVESTIGATIONAL NEW DRUGS
- Schlüsselwörter
- Apoptosis
- Cell cycle
- Drug screening
- Neoplasms
- Targeted chemotherapy
- PLK
- Paginierung
- 1 - 9
- Datum der Veröffentlichung
- 2020
- Status
- Published
- Titel
- Identification of inhibitors of the polo-box domain of polo-like kinase 1 from natural and semisynthetic compounds
- Sub types
- Article
- Ausgabe der Zeitschrift
- 38
Data source: Web of Science (Lite)
- Other metadata sources:
-
- Autoren
- Sara Abdelfatah
- Edmond Fleischer
- Anette Klinger
- Vincent Kam Wai Wong
- Thomas Efferth
- DOI
- 10.1007/s10637-019-00752-0
- eISSN
- 1573-0646
- ISSN
- 0167-6997
- Ausgabe der Veröffentlichung
- 1
- Zeitschrift
- Investigational New Drugs
- Sprache
- en
- Online publication date
- 2019
- Paginierung
- 1 - 9
- Datum der Veröffentlichung
- 2020
- Status
- Published
- Herausgeber
- Springer Science and Business Media LLC
- Herausgeber URL
- http://dx.doi.org/10.1007/s10637-019-00752-0
- Datum der Datenerfassung
- 2023
- Titel
- Identification of inhibitors of the polo-box domain of polo-like kinase 1 from natural and semisynthetic compounds
- Ausgabe der Zeitschrift
- 38
Data source: Crossref
- Abstract
- PLK1 has an important role in the regulation of cell cycle and represents an important target for cancer treatment. This enzyme belongs to the Polo-like kinases family, which is characterized by a regulatory domain named Polo-box domain (PBD). Rather than regular kinase inhibitors, this domain provides high selectivity to PLK1. Here, we report on four novel PLK1 PBD inhibitors identified by cytotoxicity screening and fluorescence polarization assay of a chemical library of natural and semisynthetic compounds. These compounds revealed two- to three-fold higher selectivity to the PDB of PLK1 than to those of the related family members, PLK2 and PLK3. These four substances inhibited tumor cell growth of sensitive CCRF-CEM and multidrug-resistant CEM/ADR5000 leukemia cells. The tested compounds increased the apoptotic cell fraction, which indicates apoptosis as a major mechanism of cell death. Cell cycle analysis showed compound (5) arrested the cell cycle of CCRF-CEM cells in the G2/M phase, while the other three molecules ((compound (3), compound (4), and compound (6)) exerted pronounced cytotoxicity with an increase of cells in the sub-G1 population. Molecular docking was performed for the understanding of ligand-protein interaction, the tested candidates showed strong binding affinity to PLK1 PBD. In conclusion, we identified four new chemical scaffolds that may serve as lead compounds for the development of selective PLK1 inhibitors in the future.
- Addresses
- Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, 55128, Mainz, Germany.
- Autoren
- Sara Abdelfatah
- Edmond Fleischer
- Anette Klinger
- Vincent Kam Wai Wong
- Thomas Efferth
- DOI
- 10.1007/s10637-019-00752-0
- eISSN
- 1573-0646
- Externe Identifier
- PubMed Identifier: 30877426
- Funding acknowledgements
- Deutscher Akademischer Austauschdienst: (57129429)
- Deutsche Forschungsgemeinschaft: INST 268/281-1 FUGG
- Open access
- false
- ISSN
- 0167-6997
- Ausgabe der Veröffentlichung
- 1
- Zeitschrift
- Investigational new drugs
- Schlüsselwörter
- Tumor Cells, Cultured
- Humans
- Leukemia, T-Cell
- Cell Cycle Proteins
- Proto-Oncogene Proteins
- Biological Products
- Protein Kinase Inhibitors
- Cell Cycle
- Apoptosis
- Cell Proliferation
- Protein Binding
- High-Throughput Screening Assays
- Molecular Docking Simulation
- Protein Serine-Threonine Kinases
- Polo-Like Kinase 1
- Sprache
- eng
- Medium
- Print-Electronic
- Online publication date
- 2019
- Paginierung
- 1 - 9
- Datum der Veröffentlichung
- 2020
- Status
- Published
- Datum der Datenerfassung
- 2019
- Titel
- Identification of inhibitors of the polo-box domain of polo-like kinase 1 from natural and semisynthetic compounds.
- Sub types
- Research Support, Non-U.S. Gov't
- Journal Article
- Ausgabe der Zeitschrift
- 38
Data source: Europe PubMed Central
- Abstract
- PLK1 has an important role in the regulation of cell cycle and represents an important target for cancer treatment. This enzyme belongs to the Polo-like kinases family, which is characterized by a regulatory domain named Polo-box domain (PBD). Rather than regular kinase inhibitors, this domain provides high selectivity to PLK1. Here, we report on four novel PLK1 PBD inhibitors identified by cytotoxicity screening and fluorescence polarization assay of a chemical library of natural and semisynthetic compounds. These compounds revealed two- to three-fold higher selectivity to the PDB of PLK1 than to those of the related family members, PLK2 and PLK3. These four substances inhibited tumor cell growth of sensitive CCRF-CEM and multidrug-resistant CEM/ADR5000 leukemia cells. The tested compounds increased the apoptotic cell fraction, which indicates apoptosis as a major mechanism of cell death. Cell cycle analysis showed compound (5) arrested the cell cycle of CCRF-CEM cells in the G2/M phase, while the other three molecules ((compound (3), compound (4), and compound (6)) exerted pronounced cytotoxicity with an increase of cells in the sub-G1 population. Molecular docking was performed for the understanding of ligand-protein interaction, the tested candidates showed strong binding affinity to PLK1 PBD. In conclusion, we identified four new chemical scaffolds that may serve as lead compounds for the development of selective PLK1 inhibitors in the future.
- Date of acceptance
- 2019
- Autoren
- Sara Abdelfatah
- Edmond Fleischer
- Anette Klinger
- Vincent Kam Wai Wong
- Thomas Efferth
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/30877426
- DOI
- 10.1007/s10637-019-00752-0
- eISSN
- 1573-0646
- Ausgabe der Veröffentlichung
- 1
- Zeitschrift
- Invest New Drugs
- Schlüsselwörter
- Apoptosis
- Cell cycle
- Drug screening
- Neoplasms
- Targeted chemotherapy, PLK
- Apoptosis
- Biological Products
- Cell Cycle
- Cell Cycle Proteins
- Cell Proliferation
- High-Throughput Screening Assays
- Humans
- Leukemia, T-Cell
- Molecular Docking Simulation
- Protein Binding
- Protein Kinase Inhibitors
- Protein Serine-Threonine Kinases
- Proto-Oncogene Proteins
- Tumor Cells, Cultured
- Polo-Like Kinase 1
- Sprache
- eng
- Country
- United States
- Paginierung
- 1 - 9
- PII
- 10.1007/s10637-019-00752-0
- Datum der Veröffentlichung
- 2020
- Status
- Published
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2020
- Titel
- Identification of inhibitors of the polo-box domain of polo-like kinase 1 from natural and semisynthetic compounds.
- Sub types
- Journal Article
- Research Support, Non-U.S. Gov't
- Ausgabe der Zeitschrift
- 38
Data source: PubMed
- Beziehungen:
- Property of