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Lookup NU author(s): Professor Akane Kawamura
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2017 The Authors 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.
Author(s): Tumber A, Nuzzi A, Hookway ES, Hatch SB, Velupillai S, Johansson C, Kawamura A, Savitsky P, Yapp C, Szykowska A, Wu N, Bountra C, Strain-Damerell C, Burgess-Brown NA, Ruda GF, Fedorov O, Munro S, England KS, Nowak RP, Schofield CJ, La Thangue NB, Pawlyn C, Davies F, Morgan G, Athanasou N, Muller S, Oppermann U, Brennan PE
Publication type: Article
Publication status: Published
Journal: Cell Chemical Biology
Year: 2017
Volume: 24
Issue: 3
Pages: 371-380
Print publication date: 16/03/2017
Online publication date: 02/03/2017
Acceptance date: 01/02/2017
Date deposited: 11/10/2019
ISSN (print): 2451-9456
ISSN (electronic): 2451-9448
Publisher: Elsevier Ltd
URL: https://doi.org/10.1016/j.chembiol.2017.02.006
DOI: 10.1016/j.chembiol.2017.02.006
PubMed id: 28262558
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