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Synthesis and Characterisation of Substrate-Based Peptides as Inhibitors of Histone Demethylase KDM4C

[ Vol. 23 , Issue. 9 ]


Simon D. Nielsen, Ulrike Leurs, Magnus Bergner, Silvia A. Barris, Kanchan Devkota, Kamilla Meyer,, Daniella Iaria, Jack McCaughan, Brian Lohse, Jesper L. Kristensen and Rasmus P. Clausen   Pages 772 - 776 ( 5 )


The design and synthesis of modified pentapeptides based on a truncated version of the substrate for KDM4C, a histone lysine demethylase (KDM), and investigation of their inhibitory activity at KDM4C is reported. By modifying the lysine residue corresponding to lysine 9 at histone 3 (H3K9), three different series of peptides were designed and synthesized. One series contained N-acylated H3K9 and two series introduced triazoles in this position via click chemistry to enable facile variation of headgroups. The click reaction is compatible with free amino acids and this was performed on an azido containing deprotected pentapeptide demonstrating a highly facile and convergent synthetic strategy for making substrate-based inhibitors. One of the 14 peptides showed inhibitory activity at KDM4C demonstrating the need for an iron chelator in the pentapeptide series.


Histone demethylase, inhibitor, substrate mimic, peptide synthesis, epigenetics, KDM4C.


Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 162, DK-2100 Copenhagen, Denmark

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