Related Experiment Video

Updated: Sep 27, 2025

Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
06:07

Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors

Published on: August 5, 2022

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Structural characterization of dicyanopyridine containing DNMT1-selective, non-nucleoside inhibitors

John R Horton1, Sarath Pathuri1, Kristen Wong2

  • 1Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Structure (London, England : 1993)
|April 8, 2022
PubMed

Insights

Researchers discovered new DNMT1 inhibitors that bind to hemimethylated DNA, stabilizing the enzyme

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • DNA methylation is crucial for maintaining genomic stability and gene expression.
  • Aberrant DNA methylation, particularly DNMT1 dysfunction, is linked to cancers like acute myeloid leukemia.
  • DNMT1 (DNA methyltransferase 1) is a key enzyme in DNA methylation maintenance.

Purpose of the Study:

  • To structurally characterize novel DNMT1-selective, reversible, non-nucleoside inhibitors.
  • To elucidate the mechanism of inhibition for these new compounds.
  • To understand how these inhibitors interact with DNMT1 and hemimethylated DNA.

Main Methods:

  • X-ray crystallography to determine the structural basis of inhibition.
  • Biochemical assays to assess inhibitor potency and selectivity.
  • Computational modeling to analyze inhibitor-DNA-enzyme interactions.

Main Results:

  • A series of 3,5-dicyanopyridine-containing inhibitors were identified, exemplified by GSK3735967.
  • Inhibitors intercalate into hemimethylated DNA via the minor groove, inducing conformational changes in the DNMT1 active-site loop.
  • GSK3735967 creates new binding sites, stabilizing the displaced active-site loop and interacting with a region for trimethylated histone H4 lysine 20.

Conclusions:

  • The study provides a structural understanding of a new class of DNMT1 inhibitors.
  • These findings represent a significant advancement in developing potent and selective non-nucleoside inhibitors of DNMT1.
  • The characterized inhibitors offer potential therapeutic strategies for cancers associated with DNMT1 dysregulation.
Keywords:
DNA intercalatorDNA methylationDNMT1dicyanopyridinehemi-methylated CpG dinucleotidenon-nucleoside inhibitors

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