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

Lookup NU author(s): Professor Akane Kawamura

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Abstract

© 2018 Elsevier Ltd. 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 metadata

Author(s): Passioura T, Bhushan B, Tumber A, Kawamura A, Suga H

Publication type: Article

Publication status: Published

Journal: Bioorganic and Medicinal Chemistry

Year: 2018

Volume: 26

Issue: 6

Pages: 1225-1231

Print publication date: 15/03/2018

Online publication date: 31/01/2018

Acceptance date: 18/01/2018

Date deposited: 14/10/2019

ISSN (print): 0968-0896

ISSN (electronic): 1464-3391

Publisher: Elsevier Ltd

URL: https://doi.org/10.1016/j.bmc.2018.01.013

DOI: 10.1016/j.bmc.2018.01.013

PubMed id: 29402611

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