期刊
NATURE COMMUNICATIONS
卷 8, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms14773
关键词
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资金
- JSPS [21000005]
- 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]
- European Union [298603]
- Wellcome Trust
- European Research Council [679479]
- St Edmund Hall Oxford
- Royal Society Dorothy Hodgkin Research Fellowship
- AbbVie
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Canadian Institutes for Health Research
- Genome Canada
- GlaxoSmithKline
- Janssen
- Lilly Canada
- Novartis Research Foundation
- Ontario Ministry of Economic Development and Innovation
- Pfizer
- Takeda
- Wellcome Trust [092809/Z/10/Z]
- EPSRC [EP/L003376/1] Funding Source: UKRI
- Engineering and Physical Sciences Research Council [EP/L003376/1] Funding Source: researchfish
- Grants-in-Aid for Scientific Research [21000005] Funding Source: KAKEN
- European Research Council (ERC) [679479] Funding Source: European Research Council (ERC)
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-epsilon-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.
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