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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.

Original publication

DOI

10.1016/j.chembiol.2017.02.006

Type

Journal article

Journal

Cell Chem Biol

Publication Date

16/03/2017

Volume

24

Pages

371 - 380

Keywords

2-oxoglutarate oxygenases, JARID1B, KDM5B, chromatin, demethylases, epigenetics, histones, lysine demethylation, myeloma, oncology, Cell Cycle Checkpoints, Cell Line, Tumor, Cell Proliferation, Cell Survival, Crystallography, X-Ray, Glycine, HeLa Cells, Histones, Humans, Kaplan-Meier Estimate, Ketoglutaric Acids, Methylation, Multiple Myeloma, Niacinamide, Protein Isoforms, Pyridines, Retinoblastoma-Binding Protein 2, Transcription Initiation Site