Investigation of Selected Flavonoid Derivatives as Potent FLT3 Inhibitors for the Potential Treatment of Acute Myeloid Leukemia.

Abstract

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.

• Authors: Shih-Chung Yen, Liang-Chieh Chen, Han-Li Huang, Sin-Ting Ngo, Yi-Wen Wu, Tony Eight Lin, Tzu-Ying Sung, Ssu-Ting Lien, Hui-Ju Tseng, Shiow-Lin Pan, Wei-Jan Huang, Kai-Cheng Hsu
• Journal: Journal of natural products (J Nat Prod) Vol. 84 Issue 1 Pg. 1-10 (01 22 2021) ISSN: 1520-6025 [Electronic] United States
• PMID: 33393294 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Flavonoids
• Protein Kinase Inhibitors
• FLT3 protein, human
• fms-Like Tyrosine Kinase 3

Topics

• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis (drug effects)
• Flavonoids (pharmacology)
• Humans
• Leukemia, Myeloid, Acute (drug therapy, genetics)
• Mutation (drug effects)
• Protein Kinase Inhibitors (chemistry, pharmacology, therapeutic use)
• Xenograft Model Antitumor Assays
• fms-Like Tyrosine Kinase 3 (antagonists & inhibitors, chemistry, genetics, pharmacology, therapeutic use)