title: A selective inhibitor and probe of the cellular functions of Jumonji C domain-containing histone demethylases.
abstract: Histone methylations are important chromatin marks that regulate gene expression, genomic stability, DNA repair, and genomic imprinting. Histone demethylases are the most recent family of histone-modifying enzymes discovered. Here, we report the characterization of a small-molecule inhibitor of Jumonji C domain-containing histone demethylases. The inhibitor derives from a structure-based design and preferentially inhibits the subfamily of trimethyl lysine demethylases. Its methyl ester prodrug, methylstat, selectively inhibits Jumonji C domain-containing his-tone demethylases in cells and may be a useful small-molecule probe of chromatin and its role in epigenetics.
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309, USA.
authors.forename: Xuelai
authors.initials: X
authors.lastname: Luo
authors.forename: Yongxiang
authors.initials: Y
authors.lastname: Liu
authors.forename: Stefan
authors.initials: S
authors.lastname: Kubicek
authors.forename: Johanna
authors.initials: J
authors.lastname: Myllyharju
authors.forename: Anthony
authors.initials: A
authors.lastname: Tumber
authors.forename: Stanley
authors.initials: S
authors.lastname: Ng
authors.forename: Ka Hing
authors.initials: KH
authors.lastname: Che
authors.forename: Jessica
authors.initials: J
authors.lastname: Podoll
authors.forename: Tom D
authors.initials: TD
authors.lastname: Heightman
authors.forename: Udo
authors.initials: U
authors.lastname: Oppermann
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
mesh_terms: D045744:Cell Line, Tumor; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004952:Esters; D056466:Histone Demethylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D024510:Muscle Development / Q000187:drug effects; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D004952:Esters; D009687:Nuclear Proteins; D011355:Prodrugs; D056466:Histone Demethylases; D056484:Jumonji Domain-Containing Histone Demethylases; C523998:KDM6A protein, human