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Highly selective inhibition of histone demethylases by de novo macrocyclic peptides

Lookup NU author(s): Professor Akane Kawamura

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© The Author(s) 2017. 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-I>-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.


Publication metadata

Author(s): Kawamura A, Munzel M, Kojima T, Yapp C, Bhushan B, Goto Y, Tumber A, Katoh T, King ONF, Passioura T, Walport LJ, Hatch SB, Madden S, Muller S, Brennan PE, Chowdhury R, Hopkinson RJ, Suga H, Schofield CJ

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2017

Volume: 8

Online publication date: 06/04/2017

Acceptance date: 01/02/2017

Date deposited: 11/10/2019

ISSN (electronic): 2041-1723

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/ncomms14773

DOI: 10.1038/ncomms14773

PubMed id: 28382930


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Funding

Funder referenceFunder name
092809/Z/10/Z
298603
679479
C8717/A18245
EP/L003376/1
RE/08/004

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