Abstract |
Inhibition of histone demethylases has within recent years advanced into a new strategy for treating cancer and other diseases. Targeting specific histone demethylases can be challenging, as the active sites of KDM1A-B and KDM4A-D histone demethylases are highly conserved. Most inhibitors developed up-to-date target either the cofactor- or substrate-binding sites of these enzymes, resulting in a lack of selectivity and off-target effects. This study describes the discovery of the first peptide-based inhibitors of KDM4 histone demethylases that do not share the histone peptide sequence or inhibit through substrate competition. Through screening of DNA-encoded peptide libraries against KDM1 and -4 histone demethylases by phage display, two cyclic peptides targeting the histone demethylase KDM4C were identified and developed as inhibitors by amino acid replacement, truncation, and chemical modifications. Hydrogen/ deuterium exchange mass spectrometry revealed that the peptide-based inhibitors target KDM4C through substrate-independent interactions located on the surface remote from the active site within less conserved regions of KDM4C. The sites discovered in this study provide a new approach of targeting KDM4C through substrate- and cofactor-independent interactions and may be further explored to develop potent selective inhibitors and biological probes for the KDM4 family.
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Authors | Ulrike Leurs, Brian Lohse, Kasper D Rand, Shonoi Ming, Erik S Riise, Philip A Cole, Jesper L Kristensen, Rasmus P Clausen |
Journal | ACS chemical biology
(ACS Chem Biol)
Vol. 9
Issue 9
Pg. 2131-8
(Sep 19 2014)
ISSN: 1554-8937 [Electronic] United States |
PMID | 25014588
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Coenzymes
- Enzyme Inhibitors
- KDM4C protein, human
- Peptide Library
- Histone Demethylases
- Jumonji Domain-Containing Histone Demethylases
- KDM1A protein, human
- KDM4A protein, human
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Topics |
- Amino Acid Sequence
- Catalytic Domain
- Cell Line
(drug effects)
- Coenzymes
- Deuterium Exchange Measurement
- Enzyme Inhibitors
(chemistry, pharmacology)
- High-Throughput Screening Assays
(methods)
- Histone Demethylases
(antagonists & inhibitors, metabolism)
- Humans
- Inhibitory Concentration 50
- Jumonji Domain-Containing Histone Demethylases
(antagonists & inhibitors, metabolism)
- Molecular Sequence Data
- Peptide Library
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