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Potent and Selective KDM5 Inhibitor Stops Cellular Demethylation of H3K4me3 at Transcription Start Sites and Proliferation of MM1S Myeloma Cells.
Tumber, Anthony; Nuzzi, Andrea; Hookway, Edward S; Hatch, Stephanie B; Velupillai, Srikannathasan; Johansson, Catrine; Kawamura, Akane; Savitsky, Pavel; Yapp, Clarence; Szykowska, Aleksandra; Wu, Na; Bountra, Chas; Strain-Damerell, Claire; Burgess-Brown, Nicola A; Ruda, Gian Filippo; Fedorov, Oleg; Munro, Shonagh; England, Katherine S; Nowak, Radoslaw P; Schofield, Christopher J; La Thangue, Nicholas B; Pawlyn, Charlotte; Davies, Faith; Morgan, Gareth; Athanasou, Nick; Müller, Susanne; Oppermann, Udo; Brennan, Paul E.
Afiliación
  • Tumber A; Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK; Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, UK.
  • Nuzzi A; Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK; Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, UK.
  • Hookway ES; NIHR Oxford Biomedical Research Unit, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK.
  • Hatch SB; Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK; Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, UK.
  • Velupillai S; Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK; Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, UK.
  • Johansson C; 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.
  • Kawamura A; 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.
  • Savitsky P; Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK.
  • Yapp C; Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK; Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, UK.
  • Szykowska A; Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK.
  • Wu N; NIHR Oxford Biomedical Research Unit, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK.
  • Bountra C; Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK.
  • Strain-Damerell C; Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK.
  • Burgess-Brown NA; Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK.
  • Ruda GF; Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK; Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, UK.
  • Fedorov O; Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK; Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, UK.
  • Munro S; Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
  • England KS; Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK; Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, UK.
  • Nowak RP; 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.
  • Schofield CJ; Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK.
  • La Thangue NB; Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
  • Pawlyn C; Division of Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.
  • Davies F; 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.
  • Morgan G; 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.
  • Athanasou N; NIHR Oxford Biomedical Research Unit, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK.
  • Müller S; 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.
  • Oppermann U; 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
  • Brennan PE; 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.
Cell Chem Biol ; 24(3): 371-380, 2017 Mar 16.
Article en En | MEDLINE | ID: mdl-28262558
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.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Histonas / Niacinamida / Proteína 2 de Unión a Retinoblastoma / Glicina Límite: Humans Idioma: En Revista: Cell Chem Biol Año: 2017 Tipo del documento: Article País de afiliación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Histonas / Niacinamida / Proteína 2 de Unión a Retinoblastoma / Glicina Límite: Humans Idioma: En Revista: Cell Chem Biol Año: 2017 Tipo del documento: Article País de afiliación: Reino Unido