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Cell Chem Biol. 2017 Mar 16;24(3):371-380. doi: 10.1016/j.chembiol.2017.02.006. Epub 2017 Mar 2.

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

Author information

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.

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

PMID:
28262558
PMCID:
PMC5361737
DOI:
10.1016/j.chembiol.2017.02.006
[Indexed for MEDLINE]
Free PMC Article

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