Structure-activity studies of a macrocyclic peptide inhibitor of histone lysine demethylase 4A. Issue 6 (15th March 2018)

• Record Type: Journal Article
• Authors: Passioura, Toby; Bhushan, Bhaskar; Tumber, Anthony; Kawamura, Akane; Suga, Hiroaki
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 6(2018)
• Page Start: 1225
• Page End: 1231
• Publication Date: 2018-03-15
• Subjects: Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.01.013
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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 (>10 12 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.