Tumber, A., Nuzzi, A., Hookway, E. S., Hatch, S. B., Velupillai, S., Johansson, C., Kawamura, A., Savitsky, P., Yapp, C., Szykowska, A., Wu, N., Bountra, C., Strain-Damerell, C., Burgess-Brown, N. A., Ruda, G. F., Fedorov, O., Munro, S., England, K. S., Nowak, R. P., Schofield, C. J., La Thangue, N. B., Pawlyn, C., Davies, F., Morgan, G., Athanasou, N., Muller, S., Oppermann, U., Brennan, P. E. (2017) Potent and Selective KDM5 Inhibitor Stops Cellular Demethylation of H3K4me3 at Transcription Start Sites and Proliferation of MM1S Myeloma Cells. Cell Chemical Biology, 24 (3). pp. 371-380. ISSN 2451-9448

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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 halfmaximal effective concentration of similar to 50 mu M 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.

Item Type:	Article
Authors (ICR Faculty only):	Davies, Faith and Morgan, Gareth
All Authors:	Tumber, A., Nuzzi, A., Hookway, E. S., Hatch, S. B., Velupillai, S., Johansson, C., Kawamura, A., Savitsky, P., Yapp, C., Szykowska, A., Wu, N., Bountra, C., Strain-Damerell, C., Burgess-Brown, N. A., Ruda, G. F., Fedorov, O., Munro, S., England, K. S., Nowak, R. P., Schofield, C. J., La Thangue, N. B., Pawlyn, C., Davies, F., Morgan, G., Athanasou, N., Muller, S., Oppermann, U., Brennan, P. E.
Additional Information:	ISI Document Delivery No.: EP5ND Times Cited: 0 Cited Reference Count: 43 Tumber, Anthony Nuzzi, Andrea Hookway, Edward S. Hatch, Stephanie B. Velupillai, Srikannathasan Johansson, Catrine Kawamura, Akane Savitsky, Pavel Yapp, Clarence Szykowska, Aleksandra Wu, Na Bountra, Chas Strain-Damerell, Claire Burgess-Brown, Nicola A. Ruda, Gian Filippo Fedorov, Oleg Munro, Shonagh England, Katherine S. Nowak, Radoslaw P. Schofield, Christopher J. La Thangue, Nicholas B. Pawlyn, Charlotte Davies, Faith Morgan, Gareth Athanasou, Nick Mueller, Susanne Oppermann, Udo Brennan, Paul E. AbbVie; Bayer Pharma AG; Boehringer Ingelheim; Canada Foundation for Innovation; Eshelman Institute for Innovation; Genome Canada; Innovative Medicines Initiative (EU/EFPIA) (ULTRA-DD grant) [115766]; Janssen; Merck; Novartis Pharma AG; Ontario Ministry of Economic Development and Innovation; Pfizer; Sao Paulo Research Foundation-FAPESP; Takeda; Wellcome Trust [092809/Z/10/Z]; Arthritis Research UK [20522]; NIHR Oxford Biomedical Research Unit; Bone Cancer Research UK; Rosetrees Trust; CRUK [C8717/A18245] The SGC is a registered charity (no. 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada, Innovative Medicines Initiative (EU/EFPIA) (ULTRA-DD grant no. 115766), Janssen, Merck, Novartis Pharma AG, Ontario Ministry of Economic Development and Innovation, Pfizer, Sao Paulo Research Foundation-FAPESP, Takeda, and Wellcome Trust (092809/Z/10/Z). Research in our laboratories is further supported through funding from Arthritis Research UK (program grant number 20522), the NIHR Oxford Biomedical Research Unit, Bone Cancer Research UK, and the Rosetrees Trust. C.J.S. is funded by CRUK (C8717/A18245). A.K. is a Royal Society Dorothy Hodgkin Research Fellow. We would like to thank Professor Peter Sonneveld and Professor Hartmut Goldschmidt for the data from the HOVON/GMMG-HD4 trial. 0 CELL PRESS CAMBRIDGE CELL CHEM BIOL
Uncontrolled Keywords:	CANCER-CELLS PENETRANT INHIBITORS HISTONE IDENTIFICATION DERIVATIVES RBP2 OPTIMIZATION EXPRESSION FAMILIES ANTIGEN
Research teams:	ICR divisions > Clinical Studies > Molecular Haematology (including Cytogenetics Group and Cell Markers) ICR divisions > Molecular Pathology > Molecular Haematology (including Cytogenetics Group and Cell Markers) Closed research groups > Myeloma Targeted Treatment
Depositing User:	Barry Jenkins
Date Deposited:	20 Apr 2017 13:43
Last Modified:	20 Apr 2017 13:43
URI:	http://publications.icr.ac.uk/id/eprint/15878

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