O-methylated flavonol as a multi-kinase inhibitor of leukemogenic kinases exhibits a potential treatment for acute myeloid leukemia

Shih Chung Yen, Yi Wen Wu, Cheng Chiao Huang, Min Wu Chao, Huang Ju Tu, Liang Chieh Chen, Tony Eight Lin, Tzu Ying Sung, Hui Ju Tseng, Jung Chun Chu, Wei Jan Huang, Chia Ron Yang, Wei Chun HuangFu, Shiow Lin Pan, Kai Cheng Hsu

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Acute myeloid leukemia (AML) is a heterogeneous disease with poor overall survival characterized by various genetic changes. The continuous activation of oncogenic pathways leads to the development of drug resistance and limits current therapeutic efficacy. Therefore, a multi-targeting inhibitor may overcome drug resistance observed in AML treatment. Recently, groups of flavonoids, such as flavones and flavonols, have been shown to inhibit a variety of kinase activities, which provides potential opportunities for further anticancer applications. Purpose: In this study, we evaluated the anticancer effects of flavonoid compounds collected from our in-house library and investigated their potential anticancer mechanisms by targeting multiple kinases for inhibition in AML cells. Methods: The cytotoxic effect of the compounds was detected by cell viability assays. The kinase inhibitory activity of the selected compound was detected by kinase-based and cell-based assays. The binding conformation and interactions were investigated by molecular docking analysis. Flow cytometry was used to evaluate the cell cycle distribution and cell apoptosis. The protein and gene expression were estimated by western blotting and qPCR, respectively. Results: In this study, an O-methylated flavonol (compound 11) was found to possess remarkable cytotoxic activity against AML cells compared to treatment in other cancer cell lines. The compound was demonstrated to act against multiple kinases, which play critical roles in survival signaling in AML, including FLT3, MNK2, RSK, DYRK2 and JAK2 with IC50 values of 1 - 2 μM. Compared to our previous flavonoid compounds, which only showed inhibitions against MNKs or FLT3, compound 11 exhibited multiple kinase inhibitory abilities. Moreover, compound 11 showed effectiveness in inhibiting internal tandem duplications of FLT3 (FLT3-ITDs), which accounts for 25% of AML cases. The interactions between compound 11 and targeted kinases were investigated by molecular docking analysis. Mechanically, compound 11 caused dose-dependent accumulation of leukemic cells at the G0/G1 phase and followed by the cells undergoing apoptosis. Conclusion: O-methylated flavonol, compound 11, can target multiple kinases, which may provide potential opportunities for the development of novel therapeutics for drug-resistant AMLs. This work provides a good starting point for further compound optimization.

Original languageEnglish
Article number154061
JournalPhytomedicine
Volume100
DOIs
Publication statusPublished - Jun 2022

Keywords

  • Acute myeloid leukemia
  • Flavonoid
  • Leukemia-related kinase
  • Molecular docking
  • Multiple kinase inhibitor

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Complementary and alternative medicine

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