Investigation of Selected Flavonoid Derivatives as Potent FLT3 Inhibitors for the Potential Treatment of Acute Myeloid Leukemia
| Autor: | Tzu Ying Sung, Liang Chieh Chen, Ssu Ting Lien, Yi Wen Wu, Sin Ting Ngo, Shiow Lin Pan, Shih Chung Yen, Hui Ju Tseng, Kai Cheng Hsu, Tony Eight Lin, Han Li Huang, Wei Jan Huang |
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| Rok vydání: | 2021 |
| Předmět: |
Pharmaceutical Science
Antineoplastic Agents Apoptosis 01 natural sciences Analytical Chemistry fluids and secretions hemic and lymphatic diseases Drug Discovery Humans Kinase activity Cytotoxicity Protein Kinase Inhibitors IC50 Flavonoids Pharmacology 010405 organic chemistry Kinase Chemistry Organic Chemistry Myeloid leukemia hemic and immune systems Xenograft Model Antitumor Assays 0104 chemical sciences Leukemia Myeloid Acute 010404 medicinal & biomolecular chemistry fms-Like Tyrosine Kinase 3 Complementary and alternative medicine Cell culture Mutation embryonic structures Cancer research Molecular Medicine G1 phase |
| Zdroj: | Journal of Natural Products. 84:1-10 |
| ISSN: | 1520-6025 0163-3864 |
| DOI: | 10.1021/acs.jnatprod.0c00589 |
| Popis: | Acute myeloid leukemia (AML) is an aggressive disease with a poor prognosis and a high degree of relapse seen in patients. Overexpression of FMS-like tyrosine kinase 3 (FLT3) is associated with up to 70% of AML patients. Wild-type FLT3 induces proliferation and inhibits apoptosis in AML cells, while uncontrolled proliferation of FLT3 kinase activity is also associated with FLT3 mutations. Therefore, inhibiting FLT3 activity is a promising AML therapy. Flavonoids are a group of phytochemicals that can target protein kinases, suggesting their potential antitumor activities. In this study, several plant-derived flavonoids have been identified with FLT3 inhibitory activity. Among these compounds, compound 40 (5,7,4'-trihydroxy-6-methoxyflavone) exhibited the most potent inhibition against not only FLT3 (IC50 = 0.44 μM) but also FLT3-D835Y and FLT3-ITD mutants (IC50 = 0.23 and 0.39 μM, respectively). The critical interactions between the FLT3 binding site and the compounds were identified by performing a structure-activity relationship analysis. Furthermore, the results of cellular assays revealed that compounds 28, 31, 32, and 40 exhibited significant cytotoxicity against two human AML cell lines (MOLM-13 and MV-4-11), and compounds 31, 32, and 40 resulted in cell apoptosis and G0/G1 cell cycle arrest. Collectively, these flavonoids have the potential to be further optimized as FLT3 inhibitors and provide valuable chemical information for the development of new AML drugs. |
| Databáze: | OpenAIRE |
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