Identification and characterization of deschloro-chlorothricin obtained from a large natural product library targeting aurora A kinase in multiple myeloma
- Publication type:
- Journal article
- Metadata:
-
- Autoren
- Nadire Ozenver
- Sara Abdelfatah
- Anette Klinger
- Edmond Fleischer
- Thomas Efferth
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000572704700002&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.1007/s10637-020-01012-2
- eISSN
- 1573-0646
- Externe Identifier
- Clarivate Analytics Document Solution ID: QX2WR
- PubMed Identifier: 32978717
- ISSN
- 0167-6997
- Ausgabe der Veröffentlichung
- 2
- Zeitschrift
- INVESTIGATIONAL NEW DRUGS
- Schlüsselwörter
- Cancer
- Multiple myeloma
- Natural product
- precision medicine
- Targeted chemotherapy
- Paginierung
- 348 - 361
- Datum der Veröffentlichung
- 2021
- Status
- Published
- Titel
- Identification and characterization of deschloro-chlorothricin obtained from a large natural product library targeting aurora A kinase in multiple myeloma
- Sub types
- Article
- Ausgabe der Zeitschrift
- 39
Data source: Web of Science (Lite)
- Other metadata sources:
-
- Abstract
- <jats:title>Summary</jats:title><jats:p>Multiple myeloma (MM) is a devastating disease with low survival rates worldwide. The mean lifetime of patients may be extendable with new drug alternatives. Aurora A kinase (AURKA) is crucial in oncogenesis, because its overexpression or amplification may incline the development of various types of cancer, including MM. Therefore, inhibitors of AURKA are innovative and promising targets. Natural compounds always represented a valuable resource for anticancer drug development. In the present study, based on virtual drug screening of more than 48,000 natural compounds, the antibiotic deschloro-chlorotricin (DCCT) has been identified to bind to AURKA with even higher binding affinity (free bindung energy: −12.25 kcal/mol) than the known AURKA inhibitor, alisertib (free binding energy: −11.25 kcal/mol). The in silico studies have been verified in vitro by using microscale thermophoresis. DCCT inhibited MM cell lines (KMS-11, L-363, RPMI-8226, MOLP-8, OPM-2, NCI-H929) with IC<jats:sub>50</jats:sub> values in a range from 0.01 to 0.12 μM. Furthermore, DCCT downregulated AURKA protein expression, induced G2/M cell cycle arrest and disturbed the cellular microtubule network as determined by Western blotting, flow cytometry, and fluorescence microscopy. Thus, DCCT may be a promising lead structure for further derivatization and the development of specific AURKA inhibitors in MM therapy.</jats:p>
- Autoren
- Nadire Özenver
- Sara Abdelfatah
- Anette Klinger
- Edmond Fleischer
- Thomas Efferth
- DOI
- 10.1007/s10637-020-01012-2
- eISSN
- 1573-0646
- ISSN
- 0167-6997
- Ausgabe der Veröffentlichung
- 2
- Zeitschrift
- Investigational New Drugs
- Sprache
- en
- Online publication date
- 2020
- Paginierung
- 348 - 361
- Datum der Veröffentlichung
- 2021
- Status
- Published
- Herausgeber
- Springer Science and Business Media LLC
- Herausgeber URL
- http://dx.doi.org/10.1007/s10637-020-01012-2
- Datum der Datenerfassung
- 2023
- Titel
- Identification and characterization of deschloro-chlorothricin obtained from a large natural product library targeting aurora A kinase in multiple myeloma
- Ausgabe der Zeitschrift
- 39
Data source: Crossref
- Abstract
- Multiple myeloma (MM) is a devastating disease with low survival rates worldwide. The mean lifetime of patients may be extendable with new drug alternatives. Aurora A kinase (AURKA) is crucial in oncogenesis, because its overexpression or amplification may incline the development of various types of cancer, including MM. Therefore, inhibitors of AURKA are innovative and promising targets. Natural compounds always represented a valuable resource for anticancer drug development. In the present study, based on virtual drug screening of more than 48,000 natural compounds, the antibiotic deschloro-chlorotricin (DCCT) has been identified to bind to AURKA with even higher binding affinity (free bindung energy: -12.25 kcal/mol) than the known AURKA inhibitor, alisertib (free binding energy: -11.25 kcal/mol). The in silico studies have been verified in vitro by using microscale thermophoresis. DCCT inhibited MM cell lines (KMS-11, L-363, RPMI-8226, MOLP-8, OPM-2, NCI-H929) with IC<sub>50</sub> values in a range from 0.01 to 0.12 μM. Furthermore, DCCT downregulated AURKA protein expression, induced G2/M cell cycle arrest and disturbed the cellular microtubule network as determined by Western blotting, flow cytometry, and fluorescence microscopy. Thus, DCCT may be a promising lead structure for further derivatization and the development of specific AURKA inhibitors in MM therapy.
- Addresses
- Department of Pharmacognosy, Faculty of Pharmacy, Hacettepe University, 06100, Ankara, Turkey.
- Autoren
- Nadire Özenver
- Sara Abdelfatah
- Anette Klinger
- Edmond Fleischer
- Thomas Efferth
- DOI
- 10.1007/s10637-020-01012-2
- eISSN
- 1573-0646
- Externe Identifier
- PubMed Identifier: 32978717
- PubMed Central ID: PMC8551148
- Funding acknowledgements
- Deutscher Akademischer Austauschdienst: 57440917
- Open access
- true
- ISSN
- 0167-6997
- Ausgabe der Veröffentlichung
- 2
- Zeitschrift
- Investigational new drugs
- Schlüsselwörter
- Cell Line, Tumor
- Humans
- Multiple Myeloma
- Azepines
- Pyrimidines
- Aminoglycosides
- Cell Cycle
- Protein Binding
- Dose-Response Relationship, Drug
- Aurora Kinase A
- Sprache
- eng
- Medium
- Print-Electronic
- Online publication date
- 2020
- Open access status
- Open Access
- Paginierung
- 348 - 361
- Datum der Veröffentlichung
- 2021
- Status
- Published
- Publisher licence
- CC BY
- Datum der Datenerfassung
- 2020
- Titel
- Identification and characterization of deschloro-chlorothricin obtained from a large natural product library targeting aurora A kinase in multiple myeloma.
- Sub types
- Research Support, Non-U.S. Gov't
- research-article
- Journal Article
- Ausgabe der Zeitschrift
- 39
Files
https://europepmc.org/articles/PMC8551148?pdf=render
Data source: Europe PubMed Central
- Abstract
- Multiple myeloma (MM) is a devastating disease with low survival rates worldwide. The mean lifetime of patients may be extendable with new drug alternatives. Aurora A kinase (AURKA) is crucial in oncogenesis, because its overexpression or amplification may incline the development of various types of cancer, including MM. Therefore, inhibitors of AURKA are innovative and promising targets. Natural compounds always represented a valuable resource for anticancer drug development. In the present study, based on virtual drug screening of more than 48,000 natural compounds, the antibiotic deschloro-chlorotricin (DCCT) has been identified to bind to AURKA with even higher binding affinity (free bindung energy: -12.25 kcal/mol) than the known AURKA inhibitor, alisertib (free binding energy: -11.25 kcal/mol). The in silico studies have been verified in vitro by using microscale thermophoresis. DCCT inhibited MM cell lines (KMS-11, L-363, RPMI-8226, MOLP-8, OPM-2, NCI-H929) with IC50 values in a range from 0.01 to 0.12 μM. Furthermore, DCCT downregulated AURKA protein expression, induced G2/M cell cycle arrest and disturbed the cellular microtubule network as determined by Western blotting, flow cytometry, and fluorescence microscopy. Thus, DCCT may be a promising lead structure for further derivatization and the development of specific AURKA inhibitors in MM therapy.
- Date of acceptance
- 2020
- Autoren
- Nadire Özenver
- Sara Abdelfatah
- Anette Klinger
- Edmond Fleischer
- Thomas Efferth
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/32978717
- DOI
- 10.1007/s10637-020-01012-2
- eISSN
- 1573-0646
- Externe Identifier
- PubMed Central ID: PMC8551148
- Ausgabe der Veröffentlichung
- 2
- Zeitschrift
- Invest New Drugs
- Schlüsselwörter
- Cancer
- Multiple myeloma
- Natural product, precision medicine
- Targeted chemotherapy
- Aminoglycosides
- Aurora Kinase A
- Azepines
- Cell Cycle
- Cell Line, Tumor
- Dose-Response Relationship, Drug
- Humans
- Multiple Myeloma
- Protein Binding
- Pyrimidines
- Sprache
- eng
- Country
- United States
- Paginierung
- 348 - 361
- PII
- 10.1007/s10637-020-01012-2
- Datum der Veröffentlichung
- 2021
- Status
- Published
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2022
- Titel
- Identification and characterization of deschloro-chlorothricin obtained from a large natural product library targeting aurora A kinase in multiple myeloma.
- Sub types
- Journal Article
- Research Support, Non-U.S. Gov't
- Ausgabe der Zeitschrift
- 39
Data source: PubMed
- Beziehungen:
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