title: Potent and Selective KDM5 Inhibitor Stops Cellular Demethylation of H3K4me3 at Transcription Start Sites and Proliferation of MM1S Myeloma Cells.
abstract: Methylation of lysine residues on histone tail is a dynamic epigenetic modification that plays a key role in chromatin structure and gene regulation. Members of the KDM5 (also known as JARID1) sub-family are 2-oxoglutarate (2-OG) and Fe2+-dependent oxygenases acting as histone 3 lysine 4 trimethyl (H3K4me3) demethylases, regulating proliferation, stem cell self-renewal, and differentiation. Here we present the characterization of KDOAM-25, an inhibitor of KDM5 enzymes. KDOAM-25 shows biochemical half maximal inhibitory concentration values of <100 nM for KDM5A-D in vitro, high selectivity toward other 2-OG oxygenases sub-families, and no off-target activity on a panel of 55 receptors and enzymes. In human cell assay systems, KDOAM-25 has a half maximal effective concentration of ∼50 μM and good selectivity toward other demethylases. KDM5B is overexpressed in multiple myeloma and negatively correlated with the overall survival. Multiple myeloma MM1S cells treated with KDOAM-25 show increased global H3K4 methylation at transcriptional start sites and impaired proliferation.
authors.affiliation: Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK; Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: Tumber
authors.affiliation: Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK; Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Nuzzi
authors.affiliation: NIHR Oxford Biomedical Research Unit, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK.
authors.forename: Edward S
authors.initials: ES
authors.lastname: Hookway
authors.affiliation: Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK; Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, UK.
authors.forename: Stephanie B
authors.initials: SB
authors.lastname: Hatch
authors.affiliation: Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK; Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, UK.
authors.forename: Srikannathasan
authors.initials: S
authors.lastname: Velupillai
authors.affiliation: NIHR Oxford Biomedical Research Unit, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK; Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK.
authors.forename: Catrine
authors.initials: C
authors.lastname: Johansson
authors.affiliation: Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Akane
authors.initials: A
authors.lastname: Kawamura
authors.affiliation: Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Pavel
authors.initials: P
authors.lastname: Savitsky
authors.affiliation: Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK; Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, UK.
authors.forename: Clarence
authors.initials: C
authors.lastname: Yapp
authors.affiliation: Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Szykowska
authors.affiliation: NIHR Oxford Biomedical Research Unit, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK.
authors.forename: Na
authors.initials: N
authors.lastname: Wu
authors.affiliation: Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Chas
authors.initials: C
authors.lastname: Bountra
authors.affiliation: Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Strain-Damerell
authors.affiliation: Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Burgess-Brown
authors.affiliation: Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK; Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, UK.
authors.forename: Gian Filippo
authors.initials: GF
authors.lastname: Ruda
authors.affiliation: Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK; Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, UK.
authors.forename: Oleg
authors.initials: O
authors.lastname: Fedorov
authors.affiliation: Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Shonagh
authors.initials: S
authors.lastname: Munro
authors.affiliation: Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK; Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, UK.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: England
authors.affiliation: Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK; NIHR Oxford Biomedical Research Unit, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK.
authors.forename: Radoslaw P
authors.initials: RP
authors.lastname: Nowak
authors.affiliation: Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Schofield
authors.affiliation: Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: La Thangue
authors.affiliation: Division of Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Pawlyn
authors.affiliation: Division of Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK; University of Arkansas for Medical Sciences, Myeloma Institute, 4301 W. Markham #816, Little Rock, AR 72205, USA.
authors.forename: Faith
authors.initials: F
authors.lastname: Davies
authors.affiliation: Division of Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK; University of Arkansas for Medical Sciences, Myeloma Institute, 4301 W. Markham #816, Little Rock, AR 72205, USA.
authors.forename: Gareth
authors.initials: G
authors.lastname: Morgan
authors.affiliation: NIHR Oxford Biomedical Research Unit, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK.
authors.forename: Nick
authors.initials: N
authors.lastname: Athanasou
authors.affiliation: Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK; Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, UK. Electronic address: susanne.muller-knapp@sgc.ox.ac.uk.
authors.forename: Susanne
authors.initials: S
authors.lastname: Müller
authors.affiliation: Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK; NIHR Oxford Biomedical Research Unit, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK. Electronic address: udo.oppermann@sgc.ox.ac.uk.
authors.forename: Udo
authors.initials: U
authors.lastname: Oppermann
authors.affiliation: Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK; Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, UK. Electronic address: paul.brennan@sgc.ox.ac.uk.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Brennan
mesh_terms: D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism*; D006801:Humans; D053208:Kaplan-Meier Estimate; D007656:Ketoglutaric Acids / Q000737:chemistry / Q000378:metabolism; D008745:Methylation; D009101:Multiple Myeloma / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D056485:Retinoblastoma-Binding Protein 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D024363:Transcription Initiation Site
chemical_list: D006657:Histones; C000624629:KDOAM-25; D007656:Ketoglutaric Acids; D020033:Protein Isoforms; D011725:Pyridines; D009536:Niacinamide; D056485:Retinoblastoma-Binding Protein 2; D005998:Glycine
keywords: 2-oxoglutarate oxygenases; JARID1B; KDM5B; chromatin; demethylases; epigenetics; histones; lysine demethylation; myeloma; oncology