Identification and characterization of deschloro-chlorothricin obtained from a large natural product library targeting a
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PRECLINICAL STUDIES
Identification and characterization of deschloro-chlorothricin obtained from a large natural product library targeting aurora A kinase in multiple myeloma Nadire Özenver 1,2
&
Sara Abdelfatah 2
&
Anette Klinger 3 & Edmond Fleischer 3 & Thomas Efferth 2
Received: 21 August 2020 / Accepted: 21 September 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Summary 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 deschlorochlorotricin (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, MOLP8, 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. Keywords Cancer . Multiple myeloma . Natural product, precision medicine . Targeted chemotherapy
* Thomas Efferth [email protected] Nadire Özenver [email protected] Sara Abdelfatah [email protected] Anette Klinger [email protected] Edmond Fleischer [email protected] 1
Department of Pharmacognosy, Faculty of Pharmacy, Hacettepe University, 06100 Ankara, Turkey
2
Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany
3
MicroCombiChem GmbH, 65203 Wiesbaden, Germany
Abbreviations AKI Aurora kinase inhibitor AURK Aurora kinase AURKA Aurora A kinase DAPI 4′,6 diamidino-2-phenylindole DCCT Deschloro-chlorotricin dlg Docking log FBS Fetal bovine serum MDR Multi-drug resistance MM Multiple myeloma MST Microscale thermophoresis NCI National Cancer Institute PDBQT Protein data bank partial charge and atom type PI Propidium iodide PIS Penicillin (100 U/ml)-streptomycin (100 μg/ml) PBS Phosphate buffered saline pKi The predicted inhibition constant SEER The Surveillance, Epidemiology, and End Results TBST Tris-buffered saline Tween 20 VMD Visual molecular dynamics
Invest New Drugs
Introduction Multiple myeloma (MM) is a crit
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