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Biological Evaluation of Selected Flavonoids as Inhibitors of MNKs Targeting Acute Myeloid Leukemia.

Abstract
Excessive eIF4E phosphorylation by mitogen-activated protein kinase (MAPK)-interacting kinases 1 and 2 (MNK1 and MNK2; collectively, MNKs) has been associated with oncogenesis. The overexpression of eIF4E in acute myeloid leukemia (AML) is related to cancer cell growth and survival. Thus, the inhibition of MNKs and eIF4E phosphorylation are potential therapeutic strategies for AML. Herein, a structure-based virtual screening approach was performed to identify potential MNK inhibitors from natural products. Three flavonoids, apigenin, hispidulin, and luteolin, showed MNK2 inhibitory activity with IC50 values of 308, 252, and 579 nM, respectively. A structure-activity relationship analysis was performed to disclose the molecular interactions. Furthermore, luteolin exhibited substantial inhibitory efficacy against MNK1 (IC50 = 179 nM). Experimental results from cellular assays showed that hispidulin and luteolin inhibited the growth of MOLM-13 and MV4-11 AML cells by downregulating eIF4E phosphorylation and arresting the cell cycle at the G0/G1 phase. Therefore, hispidulin and luteolin showed promising results as lead compounds for the potential treatment for AML.
AuthorsLiang-Chieh Chen, Han-Li Huang, Wei-Chun HuangFu, Shih-Chung Yen, 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
JournalJournal of natural products (J Nat Prod) Vol. 83 Issue 10 Pg. 2967-2975 (10 23 2020) ISSN: 1520-6025 [Electronic] United States
PMID33026809 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Flavonoids
  • Intracellular Signaling Peptides and Proteins
  • Protein Kinase Inhibitors
  • MKNK1 protein, human
  • Protein Serine-Threonine Kinases
Topics
  • Cell Cycle
  • Cell Line, Tumor
  • Flavonoids
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Leukemia, Myeloid, Acute
  • Molecular Structure
  • Phosphorylation
  • Protein Kinase Inhibitors
  • Protein Serine-Threonine Kinases
  • Structure-Activity Relationship

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