title: Epigenetic drug discovery: targeting DNA methyltransferases.
abstract: Epigenetic modification of DNA leads to changes in gene expression. DNA methyltransferases (DNMTs) comprise a family of nuclear enzymes that catalyze the methylation of CpG dinucleotides, resulting in an epigenetic methylome distinguished between normal cells and those in disease states such as cancer. Disrupting gene expression patterns through promoter methylation has been implicated in many malignancies and supports DNMTs as attractive therapeutic targets. This review focuses on the rationale of targeting DNMTs in cancer, the historical approach to DNMT inhibition, and current marketed hypomethylating therapeutics azacytidine and decitabine. In addition, we address novel DNMT inhibitory agents emerging in development, including CP-4200 and SGI-110, analogs of azacytidine and decitabine, respectively; the oligonucleotides MG98 and miR29a; and a number of reversible inhibitors, some of which appear to be selective against particular DNMT isoforms. Finally, we discuss future opportunities and challenges for next-generation therapeutics.
authors.affiliation: Astex Pharmaceuticals, Inc., Salt Lake City, UT 84109, USA. steven.kanner@astx.com
authors.forename: Jason M
authors.initials: JM
authors.lastname: Foulks
authors.forename: K Mark
authors.initials: KM
authors.lastname: Parnell
authors.forename: Rebecca N
authors.initials: RN
authors.lastname: Nix
authors.forename: Suzanna
authors.initials: S
authors.lastname: Chau
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Swierczek
authors.forename: Michael
authors.initials: M
authors.lastname: Saunders
authors.forename: Kevin
authors.initials: K
authors.lastname: Wright
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Hendrickson
authors.forename: Koc-Kan
authors.initials: KK
authors.lastname: Ho
authors.forename: Michael V
authors.initials: MV
authors.lastname: McCullar
authors.forename: Steven B
authors.initials: SB
authors.lastname: Kanner
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D019175:DNA Methylation / Q000187:drug effects; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D000077209:Decitabine; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; C551537:CP 4200; D004791:Enzyme Inhibitors; D000077209:Decitabine; D015254:DNA Modification Methylases; D001374:Azacitidine