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KDM Inhibitors 2016


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Recent Progress in Histone Demethylase Inhibitors

† Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, U.K.
‡ Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Old Road Campus, Roosevelt Drive, Headington, OX3 7BN, U.K.
§ Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Headington, OX3 7DQ, U.K.
∥ Target Discovery Institute, University of Oxford, NDM Research Building, Roosevelt Drive, Headington, OX3 7FZ, U.K.
J. Med. Chem., 2016, 59 (4), pp 1308–1329
DOI: 10.1021/acs.jmedchem.5b01758
Publication Date (Web): December 28, 2015
Copyright © 2015 American Chemical Society
*For C.J.S.: E-mail, christopher.schofield@chem.ox.ac.uk Phone, +44 (0)1865 285000, fax, +44 (0)1865 275674., *For A.K.: E-mail, akane.kawamura@chem.ox.ac.uk.
This article is part of the Epigenetics special issue.
Biography
Tom E. McAllister completed his Ph.D. in chemical biology at the University of Leeds in 2013 under the supervision of Dr. Michael E. Webb, developing methods to study labile protein post-translational modifications. He then worked as a postdoctoral fellow with Assoc. Prof. W. Bruce Turnbull, also at Leeds, to produce virus-like particles through defined protein–carbohydrate interactions. After a brief spell as a teaching fellow at the University of York, Tom began his postdoctoral position with Dr. Akane Kawamura at the University of Oxford in 2014. His current work focusses on the development of highly selective inhibitors for histone demethylases.
Biography
Katherine S. England completed an M.Chem. degree at the University of Oxford, working under the supervision of Prof. Jeremy Robertson for her final year research project. In 2002, she joined the Medicinal Chemistry department at Pfizer in Sandwich, UK, where she worked in drug discovery across a variety of disease areas and drug classes. Katherine joined the Structural Genomics Consortium at the University of Oxford in 2011, where she designed and synthesized inhibitors of epigenetic proteins and was awarded a D.Phil. in Organic Chemistry under the supervision of Prof. Christopher Schofield and Prof. Paul Brennan. In 2015, she joined the newly formed Alzheimer’s Research UK Oxford Drug Discovery Institute, where she is engaged in the design and synthesis of new molecules as potential treatments for dementia.
Biography
Richard J. Hopkinson received his D.Phil. in organic chemistry (2012) from the University of Oxford under the supervision of Prof. Christopher J. Schofield FRS, where his work focused on studying the mechanisms of histone demethylases. Following postdoctoral work on demethylase inhibition, he was elected to the William R. Miller Junior Research Fellowship in Molecular Aspects of Biology at St. Edmund Hall, Oxford, where his current research investigates the (bio)chemistry of formaldehyde in cellular systems.
Biography
Paul E. Brennan received his Ph.D. in organic chemistry from UC Berkeley, working on combinatorial chemistry and antibiotics. Following postdoctoral research in Cambridge University on total synthesis, Paul returned to California to take a position at Amgen. His research was focused on kinase inhibitors for oncology. After two years at Amgen, Paul moved to Pfizer in Sandwich, UK. In 2011, Paul joined the Structural Genomics Consortium as the Associate Professor of Medicinal Chemistry to discover chemical probes for epigenetic proteins. Since 2015, Paul has been the Head of Chemistry at the ARUK ODDI. His current research is focused on epigenetic proteins and new dementia targets.
Biography
Akane Kawamura completed her M.Chem. in Chemistry in 2000 and received her D.Phil. in Pharmacology from University of Oxford in 2005. She spent three years at Summit PLC, a biotechnology company, where she led a number of drug discovery projects across multiple therapeutic areas. In 2009, she joined Professor Chris Schofield’s laboratory to work on developing chemical probes for epigenetic proteins. She was awarded a BHF CRE Senior Fellowship in 2012 and a Royal Society Dorothy Hodgkin Research Fellowship in 2013. Her current research focuses on understanding the molecular mechanisms of epigenetic regulation by chromatin modifying enzymes.
Biography
Christopher J. Schofield’s research is driven by a desire to apply chemical principles and techniques to understanding biology. His research focuses on the functions, mechanisms, and structures of “chemically interesting” metallo-enzymes with roles ranging from antibiotic resistance to the oxygen dependent regulation of protein biosynthesis in humans.

Abstract

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There is increasing interest in targeting histone N-methyl-lysine demethylases (KDMs) with small molecules both for the generation of probes for target exploration and for therapeutic purposes. Here we update on previous reviews on the inhibition of the lysine-specific demethylases (LSDs or KDM1s) and JmjC families of N-methyl-lysine demethylases (JmjC KDMs, KDM2–7), focusing on the academic and patent literature from 2014 to date. We also highlight recent biochemical, biological, and structural studies which are relevant to KDM inhibitor development.
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Received 10 November 2015
Published online 28 December 2015
Published in print 25 February 2016
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  1. Unknown2018年10月15日 0:12

    NCGC00244536 is a potent KDM4A inhibitor (IC50= 10 nM) that inhibits the in vivo growth of tumors derived from PC3 cells and ex vivo human PCa explants. NCGC00244536

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