Abstract
SummaryMultiple 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.
Highlights
Multiple myeloma (MM) is a critical plasma cell proliferative disorder characterized by the accumulation of malignant plasma cells in the bone marrow, bone lesions and immunodeficiency causing 1% of all cancers, and 10% of hematological malignancies [1,2,3]
Based on the molecular docking results, the top 9 compounds unraveled higher binding affinities than that of alisertib (MLN8237, Milennium Pharmaceuticals, Inc., Cambridge, MA), which is a highly selective Aurora A kinase (AURKA) small-molecule inhibitor developed for the treatment of malignancies [37, 38] (Table 1)
All 9 compounds bound with higher affinity to AURKA than alisertib (Table 1)
Summary
Multiple myeloma (MM) is a critical plasma cell proliferative disorder characterized by the accumulation of malignant plasma cells in the bone marrow, bone lesions and immunodeficiency causing 1% of all cancers, and 10% of hematological malignancies [1,2,3]. Aurora kinases (AURKs) including aurora kinases A, B, and C are members of the serine/threonine kinase family and are key players involved in genetic stability during cell division [7]. They have significant roles in oncogenesis, i.e. their overexpression or amplification are involved in tumorigenesis of lung cancer, colorectal carcinoma, and melanoma. Only a small number of AKIs have been investigated in clinical trials due to their frequently high toxicity towards healthy cells [10, 11] In this regard, nature as a unique source for novel chemical scaffolds may represent a valuable repository of selective and effective compounds with few side effects. Natural compounds/products may provide ample opportunities for the discovery of novel drug leads, which may enable the design of prospective (semi)synthetic derivatives with improved pharmacological features such as AKIs
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