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