Substrate- and cofactor-independent inhibition of histone demethylase KDM4C.

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.

• 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)

Chemical References

• Coenzymes
• Enzyme Inhibitors
• KDM4C protein, human
• Peptide Library
• Histone Demethylases
• Jumonji Domain-Containing Histone Demethylases
• KDM1A protein, human
• KDM4A protein, human

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