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Hydrazones as novel epigenetic modulators: Correlation between TET 1 protein inhibition activity and their iron(II)

Milan Jakubek1, Zdeněk Kejík2, Robert Kaplánek3

  • 1BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Department of Analytical Chemistry, Faculty of Chemical Engineering, University of Chemistry and Technology, Technická 5, 166 28 Prague 6, Czech Republic; Department of Paediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Ke Karlovu 2, 121 08 Prague 2, Czech Republic.

Bioorganic Chemistry
|April 19, 2019
PubMed

Insights

Researchers investigated hydrazones as inhibitors of Ten-eleven translocation protein 1 (TET 1), crucial for gene expression. They found a strong link between hydrazone affinity for iron(II) and TET 1 inhibition, suggesting a mechanism for targeting TET 1 in diseases.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Medicinal Chemistry

Background:

  • Ten-eleven translocation protein 1 (TET 1) regulates DNA demethylation and gene expression.
  • Dysregulation of TET 1 is implicated in oncological and neurodegenerative diseases.
  • Targeting TET 1 presents a therapeutic opportunity.

Purpose of the Study:

  • To evaluate the inhibitory potential of hydrazones against TET 1.
  • To elucidate the mechanism of action for hydrazone-mediated TET 1 inhibition.

Main Methods:

  • Synthesis and characterization of acyl-, aroyl-, and heterocyclic hydrazones.
  • Assay of inhibitory activity of hydrazones (compounds 1-7) against TET 1.
  • Measurement of iron(II) binding affinity (binding constant) for the tested hydrazones.

Main Results:

  • Hydrazones demonstrated significant inhibitory activity against TET 1.
  • The tested hydrazones exhibited high affinity for iron(II) ions.
  • A strong correlation was observed between iron(II) binding affinity and TET 1 inhibitory potency (IC50 values).

Conclusions:

  • Hydrazones are effective inhibitors of TET 1.
  • The mechanism of TET 1 inhibition by these hydrazones likely involves iron(II) chelation.
  • This study provides a basis for developing novel TET 1-targeting therapeutics.
Keywords:
EpigeneticHydrazoneInhibitorIron(II) affinityTET 1 protein

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