title: Inhibition of the histone demethylase JMJD2E by 3-substituted pyridine 2,4-dicarboxylates.
abstract: Based on structural analysis of the human 2-oxoglutarate (2OG) dependent JMJD2 histone N(ε)-methyl lysyl demethylase family, 3-substituted pyridine 2,4-dicarboxylic acids were identified as potential inhibitors with possible selectivity over other human 2OG oxygenases. Microwave-assisted palladium-catalysed cross coupling methodology was developed to install a diverse set of substituents on the sterically demanding C-3 position of a pyridine 2,4-dicarboxylate scaffold. The subsequently prepared di-acids were tested for in vitro inhibition of the histone demethylase JMJD2E and another human 2OG oxygenase, prolyl-hydroxylase domain isoform 2 (PHD2, EGLN1). A subset of substitution patterns yielded inhibitors with selectivity for JMJD2E over PHD2, demonstrating that structure-based inhibitor design can enable selective inhibition of histone demethylases over related human 2OG oxygenases.
authors.affiliation: Department of Chemistry and the Oxford Centre for Integrative Systems Biology, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, United Kingdom.
authors.forename: Armin
authors.initials: A
authors.lastname: Thalhammer
authors.forename: Jasmin
authors.initials: J
authors.lastname: Mecinović
authors.forename: Christoph
authors.initials: C
authors.lastname: Loenarz
authors.forename: Anthony
authors.initials: A
authors.lastname: Tumber
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Rose
authors.forename: Tom D
authors.initials: TD
authors.lastname: Heightman
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Schofield
mesh_terms: D002264:Carboxylic Acids / Q000737:chemistry* / Q000494:pharmacology; D002384:Catalysis; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D011725:Pyridines / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D002264:Carboxylic Acids; D011725:Pyridines; D056484:Jumonji Domain-Containing Histone Demethylases; C549811:KDM4E protein, human; C023666:pyridine