Substrate- and Cofactor-independent Inhibition of Histone Demethylase KDM4C
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Ulrike Leurs, Brian Lohse, Kasper Dyrberg Rand, Shonoi Ming, Erik Skjold Riise, Philip A. Cole, Jesper Langgaard Kristensen, Rasmus Prætorius Clausen
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 KDM-4A-D histone demethylases, respectively, 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.
Original language | English |
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Journal | A C S Chemical Biology |
Volume | 9 |
Issue number | 9 |
Pages (from-to) | 2131-2138 |
Number of pages | 8 |
ISSN | 1554-8929 |
DOIs | |
Publication status | Published - 11 Jul 2014 |
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ID: 118821637