Structure-activity studies of a macrocyclic peptide inhibitor of histone lysine demethylase 4A

Publication date: Available online 31 January 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Toby Passioura, Bhaskar Bhushan, Anthony Tumber, Akane Kawamura, Hiroaki Suga
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.

Graphical abstract

http://ift.tt/2DRrRzb