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The combination of genetic code reprogramming and mRNA display is a powerful approach for the identification of macrocyclic peptides with high affinities to a target of interest. We have previously used such an approach to identify a potent inhibitor (CP2) of the human KDM4A and KDM4C lysine demethylases; important regulators of gene expression. In the present study, we have used genetic code reprogramming to synthesise very high diversity focused libraries (>1012 compounds) based on CP2 and, through affinity screening, used these to delineate the structure activity relationship of CP2 binding to KDM4A. In the course of these experiments we identified a CP2 analogue (CP2f-7) with ∼4-fold greater activity than CP2 in in vitro inhibition assays. This work will facilitate the development of more potent, selective inhibitors of lysine demethylases.

Original publication




Journal article


Bioorg Med Chem

Publication Date





1225 - 1231


Amino Acid Sequence, Enzyme Inhibitors, Humans, Inhibitory Concentration 50, Jumonji Domain-Containing Histone Demethylases, MCF-7 Cells, Microscopy, Confocal, Peptides, Cyclic, Structure-Activity Relationship