title: Enzyme kinetic studies of histone demethylases KDM4C and KDM6A: towards understanding selectivity of inhibitors targeting oncogenic histone demethylases.
abstract: To investigate ligand selectivity between the oncogenic KDM4C and tumor repressor protein KDM6A histone demethylases, KDM4C and KDM6A were enzymatically characterized, and subsequently, four compounds were tested for inhibitory effects. 2,4-dicarboxypyridine and (R)-N-oxalyl-O-benzyltyrosine (3) are both known to bind to a close KDM4C homolog and 3 binds in the part of the cavity that accommodates the side chain in position 11 of histone 3. The inhibition measurements showed significant selectivity between KDM4C and KDM6A. This demonstrates that despite very similar active site topologies, selectivity between Jumonji family histone demethylases can be obtained even with small molecule ligands.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jan B L
authors.initials: JB
authors.lastname: Kristensen
authors.forename: Anders L
authors.initials: AL
authors.lastname: Nielsen
authors.forename: Lars
authors.initials: L
authors.lastname: Jørgensen
authors.forename: Line H
authors.initials: LH
authors.lastname: Kristensen
authors.forename: Charlotte
authors.initials: C
authors.lastname: Helgstrand
authors.forename: Lina
authors.initials: L
authors.lastname: Juknaite
authors.forename: Jesper L
authors.initials: JL
authors.lastname: Kristensen
authors.forename: Jette S
authors.initials: JS
authors.lastname: Kastrup
authors.forename: Rasmus P
authors.initials: RP
authors.lastname: Clausen
authors.forename: Lars
authors.initials: L
authors.lastname: Olsen
authors.forename: Michael
authors.initials: M
authors.lastname: Gajhede
mesh_terms: D004791:Enzyme Inhibitors / Q000737:chemistry; D056466:Histone Demethylases; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007700:Kinetics; D008024:Ligands; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013379:Substrate Specificity; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors
chemical_list: D004791:Enzyme Inhibitors; C413655:KDM4C protein, human; D008024:Ligands; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D056466:Histone Demethylases; D056484:Jumonji Domain-Containing Histone Demethylases; C523998:KDM6A protein, human