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

doi:10.1016/j.phymed.2022.154061

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

Phytomedicine. 2022 Jun:100:154061. doi: 10.1016/j.phymed.2022.154061. Epub 2022 Mar 16.

Authors

Shih-Chung Yen¹, Yi-Wen Wu², Cheng-Chiao Huang³, Min-Wu Chao⁴, Huang-Ju Tu⁵, Liang-Chieh Chen⁶, Tony Eight Lin⁷, Tzu-Ying Sung⁸, Hui-Ju Tseng⁹, Jung-Chun Chu¹⁰, Wei-Jan Huang¹¹, Chia-Ron Yang¹², Wei-Chun HuangFu¹³, Shiow-Lin Pan¹⁴, Kai-Cheng Hsu¹⁵

Affiliations

¹ Warshel Institute for Computational Biology, The Chinese University of Hong Kong (Shenzhen), Shenzhen, Guangdong, China.
² Warshel Institute for Computational Biology, The Chinese University of Hong Kong (Shenzhen), Shenzhen, Guangdong, China; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
³ Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan; Division of General Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei, Taiwan.
⁴ School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan; College of Science, National Sun Yat-sen University, Kaohsiung, Taiwan.
⁵ Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
⁶ Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States.
⁷ Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Master Program in Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
⁸ Biomedical Translation Research Center, Academia Sinica, Taipei, Taiwan.
⁹ Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States.
¹⁰ Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
¹¹ Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
¹² School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.
¹³ Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan.
¹⁴ Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Drug Discovery, Taipei Medical University, Taipei, Taiwan. Electronic address: slpan@tmu.edu.tw.
¹⁵ Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Drug Discovery, Taipei Medical University, Taipei, Taiwan; Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. Electronic address: piki@tmu.edu.tw.

PMID: 35364561
DOI: 10.1016/j.phymed.2022.154061

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.

Keywords: Acute myeloid leukemia; Flavonoid; Leukemia-related kinase; Molecular docking; Multiple kinase inhibitor.

MeSH terms

Antineoplastic Agents* / pharmacology
Apoptosis
Cell Line, Tumor
Flavonoids / pharmacology
Flavonoids / therapeutic use
Flavonols / pharmacology
Flavonols / therapeutic use
Humans
Leukemia, Myeloid, Acute* / drug therapy
Leukemia, Myeloid, Acute* / metabolism
Molecular Docking Simulation
Mutation
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
fms-Like Tyrosine Kinase 3 / genetics
fms-Like Tyrosine Kinase 3 / pharmacology
fms-Like Tyrosine Kinase 3 / therapeutic use

Substances

Antineoplastic Agents
Flavonoids
Flavonols
Protein Kinase Inhibitors
fms-Like Tyrosine Kinase 3