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

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

  • J Nat Prod. 2021 Jan 22;84(1):1-10. doi: 10.1021/acs.jnatprod.0c00589.
Shih-Chung Yen 1,  Liang-Chieh Chen 1 2,  Han-Li Huang 3 4 5,  Sin-Ting Ngo 3,  Yi-Wen Wu 6,  Tony Eight Lin 2 7,  Tzu-Ying Sung 8,  Ssu-Ting Lien 2,  Hui-Ju Tseng 3,  Shiow-Lin Pan 2 3 4 5 6,  Wei-Jan Huang 3 9 10 11,  Kai-Cheng Hsu 2 3 4 5 6 12
Affiliations

Affiliations

  • 1 Warshel Institute for Computational Biology, The Chinese University of Hong Kong (Shenzhen), Shenzhen, Guangdong, People's Republic of China.
  • 2 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
  • 3 Ph.D. Program in Biotechnology Research and Development, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
  • 4 Biomedical Commercialization Center, Taipei Medical University, Taipei, Taiwan.
  • 5 TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan.
  • 6 Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
  • 7 Master Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
  • 8 Institute of Bioinformatics and Systems Biology, College of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan.
  • 9 Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
  • 10 Ph.D. Program for the Clinical Drug Discovery from Botanical Herbs, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
  • 11 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
  • 12 Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
PMID: 33393294 DOI: 10.1021/acs.jnatprod.0c00589
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.

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