2. Academic Validation
  3. Potent and Selective KDM5 Inhibitor Stops Cellular Demethylation of H3K4me3 at Transcription Start Sites and Proliferation of MM1S Myeloma Cells

Potent and Selective KDM5 Inhibitor Stops Cellular Demethylation of H3K4me3 at Transcription Start Sites and Proliferation of MM1S Myeloma Cells

  • Cell Chem Biol. 2017 Mar 16;24(3):371-380. doi: 10.1016/j.chembiol.2017.02.006.
Anthony Tumber 1,  Andrea Nuzzi 1,  Edward S Hookway 2,  Stephanie B Hatch 1,  Srikannathasan Velupillai 1,  Catrine Johansson 3,  Akane Kawamura 4,  Pavel Savitsky 5,  Clarence Yapp 1,  Aleksandra Szykowska 5,  Na Wu 2,  Chas Bountra 5,  Claire Strain-Damerell 5,  Nicola A Burgess-Brown 5,  Gian Filippo Ruda 1,  Oleg Fedorov 1,  Shonagh Munro 6,  Katherine S England 1,  Radoslaw P Nowak 7,  Christopher J Schofield 8,  Nicholas B La Thangue 6,  Charlotte Pawlyn 9,  Faith Davies 10,  Gareth Morgan 10,  Nick Athanasou 2,  Susanne Müller 11,  Udo Oppermann 12,  Paul E Brennan 13
Affiliations

Affiliations

  • 1 Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK; Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, UK.
  • 2 NIHR Oxford Biomedical Research Unit, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK.
  • 3 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.
  • 4 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.
  • 5 Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK.
  • 6 Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
  • 7 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.
  • 8 Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK.
  • 9 Division of Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.
  • 10 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.
  • 11 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.
  • 12 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.
  • 13 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.
PMID: 28262558 DOI: 10.1016/j.chembiol.2017.02.006
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.

Keywords

2-oxoglutarate oxygenases; JARID1B; KDM5B; chromatin; demethylases; epigenetics; histones; lysine demethylation; myeloma; oncology.

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