title: Current limitations and future opportunities for epigenetic therapies.
abstract: This article reviews progress in epigenetic therapies that hope to improve the treatment of cancer. Tumors show widespread, aberrant epigenetic changes, leading to changes in the expression of genes involved in all the hallmarks of cancer. These epigenetic changes can potentially be reversed using small-molecule inhibitors of enzymes involved in maintenance of the epigenetic state. DNA-demethylating agents and histone deacetylase inhibitors have shown anti-tumor activity against certain hematological malignancies; however, their activity in solid tumors remains more uncertain. Major challenges remain in delivery of epigenetic therapy, maintenance of a pharmacodynamic response and achievement of a therapeutic index. We believe histone lysine methyl transferases are a highly promising epigenetic target, which has yet to be clinically exploited. Crystallographic studies on histone lysine methyl transferases provide insights into their mechanism and specificity crucial for the design and development of small-molecule inhibitors.
authors.affiliation: Imperial College London, South Kensington Campus, Department of Chemistry, London SW7 2AZ, UK.
authors.forename: F
authors.initials: F
authors.lastname: Cherblanc
authors.forename: N
authors.initials: N
authors.lastname: Chapman-Rothe
authors.forename: R
authors.initials: R
authors.lastname: Brown
authors.forename: M J
authors.initials: MJ
authors.lastname: Fuchter
mesh_terms: D000818:Animals; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D057890:Epigenomics; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000628:therapy*; D054852:Small Molecule Libraries / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D054852:Small Molecule Libraries; D004248:DNA (Cytosine-5-)-Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D006655:Histone Deacetylases