University of Leicester
Browse
- No file added yet -

Highly selective inhibition of histone demethylases by de novo macrocyclic peptides.

Download (1.69 MB)
journal contribution
posted on 2018-07-23, 10:37 authored by Akane Kawamura, Martin Münzel, Tatsuya Kojima, Clarence Yapp, Bhaskar Bhushan, Yuki Goto, Anthony Tumber, Takayuki Katoh, Oliver N. F. King, Toby Passioura, Louise J. Walport, Stephanie B. Hatch, Sarah Madden, Susanne Müller, Paul E. Brennan, Rasheduzzaman Chowdhury, Richard J. Hopkinson, Hiroaki Suga, Christopher J. Schofield
The JmjC histone demethylases (KDMs) are linked to tumour cell proliferation and are current cancer targets; however, very few highly selective inhibitors for these are available. Here we report cyclic peptide inhibitors of the KDM4A-C with selectivity over other KDMs/2OG oxygenases, including closely related KDM4D/E isoforms. Crystal structures and biochemical analyses of one of the inhibitors (CP2) with KDM4A reveals that CP2 binds differently to, but competes with, histone substrates in the active site. Substitution of the active site binding arginine of CP2 to N-ɛ-trimethyl-lysine or methylated arginine results in cyclic peptide substrates, indicating that KDM4s may act on non-histone substrates. Targeted modifications to CP2 based on crystallographic and mass spectrometry analyses results in variants with greater proteolytic robustness. Peptide dosing in cells manifests KDM4A target stabilization. Although further development is required to optimize cellular activity, the results reveal the feasibility of highly selective non-metal chelating, substrate-competitive inhibitors of the JmjC KDMs.

Funding

This work was supported by the JSPS Grant-in-Aid for the Specially Promoted Research (21000005), the Core Research for Evolutional Science and Technology (CREST) Program of Japan Science and Technology Agency (JST), BHF Centre of Research Excellence Oxford (RE/08/004), Engineering and Physical Sciences Research Council (EP/L003376/1), Cancer Research UK (C8717/A18245), the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007–2013) under REA grant agreement number 298603 (Marie Curie IEF Fellowship to M.M.), the Wellcome Trust, and the European Research Council Starter Grant (679479). R.J.H. acknowledges a William R Miller Junior Research Fellowship from St Edmund Hall Oxford and A.K. is supported by the Royal Society Dorothy Hodgkin Research Fellowship. The SGC is a registered charity (number 1097737) that receives funds from AbbVie, Boehringer Ingelheim, the Canada Foundation for Innovation, the Canadian Institutes for Health Research, Genome Canada, GlaxoSmithKline, Janssen, Lilly Canada, the Novartis Research Foundation, the Ontario Ministry of Economic Development and Innovation, Pfizer, Takeda and the Wellcome Trust (092809/Z/ 10/Z).

History

Citation

Nature Communications, 2017, 8, 14773

Author affiliation

/Organisation/COLLEGE OF SCIENCE AND ENGINEERING/Department of Chemistry

Version

  • VoR (Version of Record)

Published in

Nature Communications

Publisher

Nature Publishing Group

eissn

2041-1723

Acceptance date

2017-02-01

Copyright date

2017

Available date

2018-07-23

Publisher DOI

Publisher version

https://www.nature.com/articles/ncomms14773

Notes

The crystal structures KDM4A.Ni(II).CP2 and KDN4A.- Ni(II).CP2(R6Kme3) have been deposited under PDB accession codes 5LY1 and 5LY2, respectively. All other data are available from the authors upon reasonable request.

Language

en

Administrator link

Usage metrics

    University of Leicester Publications

    Categories

    No categories selected

    Keywords

    IR content

    Licence

    CC BY 4.0

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC