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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
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

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
Diamond Keywords: Blood Cancer; Epigenetics; Enzymes
Subject Areas:
Biology and Bio-materials,
Chemistry,
Medicine
Instruments:
I02-Macromolecular Crystallography
Added On:
08/03/2017 08:59
Documents:
1-s2.0-S2451945617300363-main.pdf
Discipline Tags:
Non-Communicable Diseases
Health & Wellbeing
Cancer
Biochemistry
Genetics
Chemistry
Structural biology
Drug Discovery
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)