Betulin, a Newly Characterized Compound in Acacia auriculiformis Bark, Is a Multi-Target Protein Kinase Inhibitor

Molecules. 2021 Jul 29;26(15):4599. doi: 10.3390/molecules26154599.

Abstract

The purpose of this work is to investigate the protein kinase inhibitory activity of constituents from Acacia auriculiformis stem bark. Column chromatography and NMR spectroscopy were used to purify and characterize betulin from an ethyl acetate soluble fraction of acacia bark. Betulin, a known inducer of apoptosis, was screened against a panel of 16 disease-related protein kinases. Betulin was shown to inhibit Abelson murine leukemia viral oncogene homolog 1 (ABL1) kinase, casein kinase 1ε (CK1ε), glycogen synthase kinase 3α/β (GSK-3 α/β), Janus kinase 3 (JAK3), NIMA Related Kinase 6 (NEK6), and vascular endothelial growth factor receptor 2 kinase (VEGFR2) with activities in the micromolar range for each. The effect of betulin on the cell viability of doxorubicin-resistant K562R chronic myelogenous leukemia cells was then verified to investigate its putative use as an anti-cancer compound. Betulin was shown to modulate the mitogen-activated protein (MAP) kinase pathway, with activity similar to that of imatinib mesylate, a known ABL1 kinase inhibitor. The interaction of betulin and ABL1 was studied by molecular docking, revealing an interaction of the inhibitor with the ABL1 ATP binding pocket. Together, these data demonstrate that betulin is a multi-target inhibitor of protein kinases, an activity that can contribute to the anticancer properties of the natural compound and to potential treatments for leukemia.

Keywords: Acacia stem bark; polypharmacology; protein kinase inhibitors; triterpenoids.

MeSH terms

  • Acacia / chemistry*
  • Antineoplastic Agents, Phytogenic / chemistry
  • Antineoplastic Agents, Phytogenic / isolation & purification
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Binding Sites
  • Casein Kinase 1 epsilon / antagonists & inhibitors
  • Casein Kinase 1 epsilon / genetics
  • Casein Kinase 1 epsilon / metabolism
  • Cell Proliferation / drug effects
  • Fusion Proteins, bcr-abl / antagonists & inhibitors
  • Fusion Proteins, bcr-abl / genetics
  • Fusion Proteins, bcr-abl / metabolism
  • Gene Expression Regulation, Leukemic / drug effects*
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 / genetics
  • Glycogen Synthase Kinase 3 / metabolism
  • Humans
  • Janus Kinase 3 / antagonists & inhibitors
  • Janus Kinase 3 / genetics
  • Janus Kinase 3 / metabolism
  • K562 Cells
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 3 / genetics
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Models, Molecular
  • NIMA-Related Kinases / antagonists & inhibitors
  • NIMA-Related Kinases / genetics
  • NIMA-Related Kinases / metabolism
  • Plant Bark / chemistry
  • Plant Extracts / chemistry
  • Protein Binding
  • Protein Conformation
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / isolation & purification
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-abl / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-abl / chemistry
  • Proto-Oncogene Proteins c-abl / genetics
  • Proto-Oncogene Proteins c-abl / metabolism
  • Signal Transduction
  • Triterpenes / chemistry
  • Triterpenes / isolation & purification
  • Triterpenes / pharmacology*
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
  • Vascular Endothelial Growth Factor Receptor-2 / genetics
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Antineoplastic Agents, Phytogenic
  • BCR-ABL1 fusion protein, human
  • Plant Extracts
  • Protein Kinase Inhibitors
  • Triterpenes
  • betulin
  • KDR protein, human
  • Vascular Endothelial Growth Factor Receptor-2
  • ABL1 protein, human
  • Fusion Proteins, bcr-abl
  • JAK3 protein, human
  • Janus Kinase 3
  • Proto-Oncogene Proteins c-abl
  • Casein Kinase 1 epsilon
  • NEK6 protein, human
  • NIMA-Related Kinases
  • MAPK1 protein, human
  • MAPK3 protein, human
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Glycogen Synthase Kinase 3
  • glycogen synthase kinase 3 alpha