Epigenetic reactivation of tumor suppressor genes by a novel small-molecule inhibitor of human DNA methyltransferases

Cancer Res. 2005 Jul 15;65(14):6305-11. doi: 10.1158/0008-5472.CAN-04-2957.


DNA methylation regulates gene expression in normal and malignant cells. The possibility to reactivate epigenetically silenced genes has generated considerable interest in the development of DNA methyltransferase inhibitors. Here, we provide a detailed characterization of RG108, a novel small molecule that effectively blocked DNA methyltransferases in vitro and did not cause covalent enzyme trapping in human cell lines. Incubation of cells with low micromolar concentrations of the compound resulted in significant demethylation of genomic DNA without any detectable toxicity. Intriguingly, RG108 caused demethylation and reactivation of tumor suppressor genes, but it did not affect the methylation of centromeric satellite sequences. These results establish RG108 as a DNA methyltransferase inhibitor with fundamentally novel characteristics that will be particularly useful for the experimental modulation of epigenetic gene regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • DNA Methylation / drug effects
  • DNA Modification Methylases / antagonists & inhibitors*
  • Enzyme Inhibitors / pharmacology*
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Genes, Tumor Suppressor / drug effects*
  • HCT116 Cells
  • Humans
  • Indoles / pharmacology*
  • Phthalimides
  • Propionates / pharmacology*
  • Tryptophan / analogs & derivatives


  • Enzyme Inhibitors
  • Indoles
  • Phthalimides
  • Propionates
  • RG108
  • Tryptophan
  • DNA Modification Methylases