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

DOI: 10.1016/j.chembiol.2017.02.006 DOI Help

Authors: Anthony Tumber (Structural Genomics Consortium, University of Oxford; Target Discovery Institute) , Andrea Nuzzi (Structural Genomics Consortium, University of Oxford; Target Discovery Institute) , Edward S. Hookway (University of Oxford) , Stephanie B. Hatch (Structural Genomics Consortium, University of Oxford; Target Discovery Institute) , Srikannathasan Velupillai (Structural Genomics Consortium, University of Oxford; Target Discovery Institute) , Catrine Johansson (University of Oxford) , Akane Kawamura (University of Oxford) , Pavel Savitsky (Structural Genomics Consortium, University of Oxford) , Clarence Yapp (Structural Genomics Consortium, University of Oxford; Target Discovery Institute) , Aleksandra Szykowska (Structural Genomics Consortium, University of Oxford) , Na Wu (University of Oxford) , Chas Bountra (Structural Genomics Consortium, University of Oxford) , Claire Strain-damerell (Structural Genomics Consortium, University of Oxford) , Nicola A. Burgess-brown (Structural Genomics Consortium, University of Oxford) , Gian Filippo Ruda (Structural Genomics Consortium, University of Oxford; Target Discovery Institute) , Oleg Fedorov (Structural Genomics Consortium, University of Oxford; Target Discovery Institute) , Shonagh Munro (University of Oxford) , Katherine S. England (Structural Genomics Consortium, University of Oxford; Target Discovery Institute) , Radoslaw P. Nowak (Structural Genomics Consortium, University of Oxford) , Christopher J. Schofield (University of Oxford) , Nicholas B. La Thangue (University of Oxford) , Charlotte Pawlyn (Institute of Cancer Research) , Faith Davies (Institute of Cancer Research; Myeloma Institute) , Gareth Morgan (Institute of Cancer Research; Myeloma Institute) , Nick Athanasou (University of Oxford) , Susanne Müller (Structural Genomics Consortium, University of Oxford; Target Discovery Institute) , Udo Oppermann (Structural Genomics Consortium, University of Oxford) , Paul E. Brennan (Structural Genomics Consortium, University of Oxford; Target Discovery Institute)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Cell Chemical Biology

State: Published (Approved)
Published: March 2017

Open Access Open Access

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.

Journal Keywords: chromatin; epigenetics; histones; lysine demethylation; demethylases; KDM5B; JARID1B; 2-oxoglutarate oxygenases; oncology; myeloma

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I02-Macromolecular Crystallography

Documents:
1-s2.0-S2451945617300363-main.pdf