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

Bioorg Med Chem. 2018 Mar 15;26(6):1225-1231. doi: 10.1016/j.bmc.2018.01.013. Epub 2018 Jan 31.

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 (>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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Humans
  • Inhibitory Concentration 50
  • Jumonji Domain-Containing Histone Demethylases / antagonists & inhibitors*
  • Jumonji Domain-Containing Histone Demethylases / metabolism
  • MCF-7 Cells
  • Microscopy, Confocal
  • Peptides, Cyclic / chemical synthesis
  • Peptides, Cyclic / chemistry*
  • Peptides, Cyclic / metabolism
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • KDM4C protein, human
  • Peptides, Cyclic
  • Jumonji Domain-Containing Histone Demethylases
  • KDM4A protein, human