title: A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response.
abstract: The jumonji (JMJ) family of histone demethylases are Fe2+- and α-ketoglutarate-dependent oxygenases that are essential components of regulatory transcriptional chromatin complexes. These enzymes demethylate lysine residues in histones in a methylation-state and sequence-specific context. Considerable effort has been devoted to gaining a mechanistic understanding of the roles of histone lysine demethylases in eukaryotic transcription, genome integrity and epigenetic inheritance, as well as in development, physiology and disease. However, because of the absence of any selective inhibitors, the relevance of the demethylase activity of JMJ enzymes in regulating cellular responses remains poorly understood. Here we present a structure-guided small-molecule and chemoproteomics approach to elucidating the functional role of the H3K27me3-specific demethylase subfamily (KDM6 subfamily members JMJD3 and UTX). The liganded structures of human and mouse JMJD3 provide novel insight into the specificity determinants for cofactor, substrate and inhibitor recognition by the KDM6 subfamily of demethylases. We exploited these structural features to generate the first small-molecule catalytic site inhibitor that is selective for the H3K27me3-specific JMJ subfamily. We demonstrate that this inhibitor binds in a novel manner and reduces lipopolysaccharide-induced proinflammatory cytokine production by human primary macrophages, a process that depends on both JMJD3 and UTX. Our results resolve the ambiguity associated with the catalytic function of H3K27-specific JMJs in regulating disease-relevant inflammatory responses and provide encouragement for designing small-molecule inhibitors to allow selective pharmacological intervention across the JMJ family.
authors: Epinova DPU, Immuno-Inflammation Therapy Area, GlaxoSmithKline R&D, Medicines Research Centre, Stevenage SG1 2NY, UK.
authors: Laurens
authors: L
authors: Kruidenier
authors: Chun-wa
authors: CW
authors: Chung
authors: Zhongjun
authors: Z
authors: Cheng
authors: John
authors: J
authors: Liddle
authors: KaHing
authors: K
authors: Che
authors: Gerard
authors: G
authors: Joberty
authors: Marcus
authors: M
authors: Bantscheff
authors: Chas
authors: C
authors: Bountra
authors: Angela
authors: A
authors: Bridges
authors: Hawa
authors: H
authors: Diallo
authors: Dirk
authors: D
authors: Eberhard
authors: Sue
authors: S
authors: Hutchinson
authors: Emma
authors: E
authors: Jones
authors: Roy
authors: R
authors: Katso
authors: Melanie
authors: M
authors: Leveridge
authors: Palwinder K
authors: PK
authors: Mander
authors: Julie
authors: J
authors: Mosley
authors: Cesar
authors: C
authors: Ramirez-Molina
authors: Paul
authors: P
authors: Rowland
authors: Christopher J
authors: CJ
authors: Schofield
authors: Robert J
authors: RJ
authors: Sheppard
authors: Julia E
authors: JE
authors: Smith
authors: Catherine
authors: C
authors: Swales
authors: Robert
authors: R
authors: Tanner
authors: Pamela
authors: P
authors: Thomas
authors: Anthony
authors: A
authors: Tumber
authors: Gerard
authors: G
authors: Drewes
authors: Udo
authors: U
authors: Oppermann
authors: Dinshaw J
authors: DJ
authors: Patel
authors: Kevin
authors: K
authors: Lee
authors: David M
authors: DM
authors: Wilson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D055162:Biocatalysis / Q000187:drug effects; D020134:Catalytic Domain; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D019143:Evolution, Molecular; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000145:classification / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D051379:Mice; D008958:Models, Molecular; D013379:Substrate Specificity; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D004791:Enzyme Inhibitors; D006657:Histones; D014409:Tumor Necrosis Factor-alpha; D056484:Jumonji Domain-Containing Histone Demethylases; C524220:KDM6B protein, human; C523761:Kdm6b protein, mouse; D008239:Lysine