title: Structural analysis of human KDM5B guides histone demethylase inhibitor development.
abstract: Members of the KDM5 (also known as JARID1) family are 2-oxoglutarate- and Fe(2+)-dependent oxygenases that act as histone H3K4 demethylases, thereby regulating cell proliferation and stem cell self-renewal and differentiation. Here we report crystal structures of the catalytic core of the human KDM5B enzyme in complex with three inhibitor chemotypes. These scaffolds exploit several aspects of the KDM5 active site, and their selectivity profiles reflect their hybrid features with respect to the KDM4 and KDM6 families. Whereas GSK-J1, a previously identified KDM6 inhibitor, showed about sevenfold less inhibitory activity toward KDM5B than toward KDM6 proteins, KDM5-C49 displayed 25-100-fold selectivity between KDM5B and KDM6B. The cell-permeable derivative KDM5-C70 had an antiproliferative effect in myeloma cells, leading to genome-wide elevation of H3K4me3 levels. The selective inhibitor GSK467 exploited unique binding modes, but it lacked cellular potency in the myeloma system. Taken together, these structural leads deliver multiple starting points for further rational and selective inhibitor design.
authors.affiliation: Structural Genomics Consortium, University of Oxford, Headington, UK.|Botnar Research Centre, NIHR Oxford Biomedical Research Unit, University of Oxford, Oxford, UK.
authors.forename: Catrine
authors.initials: C
authors.lastname: Johansson
authors.affiliation: Structural Genomics Consortium, University of Oxford, Headington, UK.
authors.forename: Srikannathasan
authors.initials: S
authors.lastname: Velupillai
authors.affiliation: Structural Genomics Consortium, University of Oxford, Headington, UK.|Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: Tumber
authors.affiliation: Structural Genomics Consortium, University of Oxford, Headington, UK.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Szykowska
authors.affiliation: Botnar Research Centre, NIHR Oxford Biomedical Research Unit, University of Oxford, Oxford, UK.
authors.forename: Edward S
authors.initials: ES
authors.lastname: Hookway
authors.affiliation: Structural Genomics Consortium, University of Oxford, Headington, UK.|Botnar Research Centre, NIHR Oxford Biomedical Research Unit, University of Oxford, Oxford, UK.
authors.forename: Radoslaw P
authors.initials: RP
authors.lastname: Nowak
authors.affiliation: Structural Genomics Consortium, University of Oxford, Headington, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Strain-Damerell
authors.affiliation: Structural Genomics Consortium, University of Oxford, Headington, UK.
authors.forename: Carina
authors.initials: C
authors.lastname: Gileadi
authors.affiliation: Botnar Research Centre, NIHR Oxford Biomedical Research Unit, University of Oxford, Oxford, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Philpott
authors.affiliation: Structural Genomics Consortium, University of Oxford, Headington, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Burgess-Brown
authors.affiliation: Botnar Research Centre, NIHR Oxford Biomedical Research Unit, University of Oxford, Oxford, UK.
authors.forename: Na
authors.initials: N
authors.lastname: Wu
authors.affiliation: Structural Genomics Consortium, University of Oxford, Headington, UK.
authors.forename: Jola
authors.initials: J
authors.lastname: Kopec
authors.affiliation: Structural Genomics Consortium, University of Oxford, Headington, UK.|Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Nuzzi
authors.affiliation: Bayer Healthcare Pharmaceuticals, Berlin, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Steuber
authors.affiliation: Bayer Healthcare Pharmaceuticals, Berlin, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Egner
authors.affiliation: Bayer Healthcare Pharmaceuticals, Berlin, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Badock
authors.affiliation: Department of Oncology, University of Oxford, Oxford, UK.
authors.forename: Shonagh
authors.initials: S
authors.lastname: Munro
authors.affiliation: Department of Oncology, University of Oxford, Oxford, UK.
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: LaThangue
authors.affiliation: Epinova DPU, Immuno-Inflammation Therapy Area, GlaxoSmithKline R&D, Stevenage, UK.
authors.forename: Sue
authors.initials: S
authors.lastname: Westaway
authors.affiliation: Epinova DPU, Immuno-Inflammation Therapy Area, GlaxoSmithKline R&D, Stevenage, UK.
authors.forename: Jack
authors.initials: J
authors.lastname: Brown
authors.affiliation: Botnar Research Centre, NIHR Oxford Biomedical Research Unit, University of Oxford, Oxford, UK.
authors.forename: Nick
authors.initials: N
authors.lastname: Athanasou
authors.affiliation: Epinova DPU, Immuno-Inflammation Therapy Area, GlaxoSmithKline R&D, Stevenage, UK.
authors.forename: Rab
authors.initials: R
authors.lastname: Prinjha
authors.affiliation: Structural Genomics Consortium, University of Oxford, Headington, UK.|Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Brennan
authors.affiliation: Structural Genomics Consortium, University of Oxford, Headington, UK.|Botnar Research Centre, NIHR Oxford Biomedical Research Unit, University of Oxford, Oxford, UK.
authors.forename: Udo
authors.initials: U
authors.lastname: Oppermann
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D056466:Histone Demethylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D012097:Repressor Proteins / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009687:Nuclear Proteins; D012097:Repressor Proteins; D056466:Histone Demethylases; D056484:Jumonji Domain-Containing Histone Demethylases; C119611:KDM5B protein, human