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
  • 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.