Substrate- and Cofactor-independent Inhibition of Histone Demethylase KDM4C

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• 作者：Ulrike Leurs ; Brian Lohse ; Kasper D. Rand ; Shonoi Ming ; Erik S. Riise ; Philip A. Cole ; Jesper L. Kristensen ; Rasmus P. Clausen
• 刊名：ACS Chemical Biology
• 出版年：2014
• 出版时间：September 19, 2014
• 年：2014
• 卷：9
• 期：9
• 页码：2131-2138
• 全文大小：339K
• ISSN：1554-8937

文摘

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.