DNA methyltransferase inhibitors: an updated patent review (2012-2015)

Expert Opin Ther Pat. 2016 Sep;26(9):1017-30. doi: 10.1080/13543776.2016.1209488. Epub 2016 Jul 18.


Introduction: DNA methyltransferases (DNMTs), important enzymes involved in epigenetic regulation of gene expression, represent promising targets in cancer therapy. DNMT inhibitors (DNMTi), which can modulate the aberrant DNA methylation pattern in a reversible way via inhibiting DNMT activity, have attracted significant attention in recent years.

Areas covered: This review outlines the newly patented inhibitors targeting DNMTs, mainly incorporating small molecular inhibitors and oligonucleotide derivatives. The chemical structures, biological activity, and the encouraging clinical research in progress are delineated in detail.

Expert opinion: Two drugs, azacitidine and decitabine, have evidently shown efficacy in hematologic malignancies, yet do not work well on solid tumors, have low specificity, substantial toxicity, and poor bioavailability. With the rapid advancement in systems biology, drug combinations, such as DNMTi, in conjugation with histone deacetylase inhibitors (HDACi) or immunotherapy, probably serve as an efficient way of implementing epigenetic therapy. Meanwhile, the resolved autoinhibitory structures of DNMTs afford a novel strategy for targeting the protein-protein interface involved in the autoinhi-bitory interactions. The molecular mechanism underlying the conformational transitions would also shed new light on the design of allosteric inhibitors. Both strategies would produce inhibitors with more selectivity compared to nucleotide derivatives.

Keywords: DNMT inhibitors (DNMTi); allosteric inhibitor; drug combination; epigenetic therapy; nucleotide derivatives.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacology*
  • DNA Modification Methylases / antagonists & inhibitors*
  • Drug Design
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / pharmacology
  • Epigenesis, Genetic
  • Gene Expression Regulation, Neoplastic / drug effects
  • Histone Deacetylase Inhibitors / administration & dosage
  • Histone Deacetylase Inhibitors / pharmacology
  • Humans
  • Immunotherapy / methods
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Patents as Topic


  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • DNA Modification Methylases