Highly selective inhibition of histone demethylases by de novo macrocyclic peptides

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 () and Christopher J. Schofield ()
Additional contact information
Akane Kawamura: Chemistry Research Laboratory, University of Oxford
Martin Münzel: Chemistry Research Laboratory, University of Oxford
Tatsuya Kojima: Graduate School of Science, The University of Tokyo
Clarence Yapp: Structural Genomics Consortium, University of Oxford
Bhaskar Bhushan: Chemistry Research Laboratory, University of Oxford
Yuki Goto: Graduate School of Science, The University of Tokyo
Anthony Tumber: Structural Genomics Consortium, University of Oxford
Takayuki Katoh: Graduate School of Science, The University of Tokyo
Oliver N. F. King: Chemistry Research Laboratory, University of Oxford
Toby Passioura: Graduate School of Science, The University of Tokyo
Louise J. Walport: Chemistry Research Laboratory, University of Oxford
Stephanie B. Hatch: Structural Genomics Consortium, University of Oxford
Sarah Madden: Chemistry Research Laboratory, University of Oxford
Susanne Müller: Structural Genomics Consortium, University of Oxford
Paul E. Brennan: Structural Genomics Consortium, University of Oxford
Rasheduzzaman Chowdhury: Chemistry Research Laboratory, University of Oxford
Richard J. Hopkinson: Chemistry Research Laboratory, University of Oxford
Hiroaki Suga: Graduate School of Science, The University of Tokyo
Christopher J. Schofield: Chemistry Research Laboratory, University of Oxford

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: Abstract 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.

Date: 2017
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/ncomms14773 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14773

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms14773

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().