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Discovery of a Highly Selective Cell-Active Inhibitor of the Histone Lysine Demethylases KDM2/7

Lookup NU author(s): Professor Akane Kawamura

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. Histone lysine demethylases (KDMs) are of critical importance in the epigenetic regulation of gene expression, yet there are few selective, cell-permeable inhibitors or suitable tool compounds for these enzymes. We describe the discovery of a new class of inhibitor that is highly potent towards the histone lysine demethylases KDM2A/7A. A modular synthetic approach was used to explore the chemical space and accelerate the investigation of key structure–activity relationships, leading to the development of a small molecule with around 75-fold selectivity towards KDM2A/7A versus other KDMs, as well as cellular activity at low micromolar concentrations.

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Author(s): Gerken PA, Wolstenhulme JR, Tumber A, Hatch SB, Zhang Y, Muller S, Chandler SA, Mair B, Li F, Nijman SMB, Konietzny R, Szommer T, Yapp C, Fedorov O, Benesch JLP, Vedadi M, Kessler BM, Kawamura A, Brennan PE, Smith MD

Publication type: Article

Publication status: Published

Journal: Angewandte Chemie - International Edition

Year: 2017

Volume: 56

Issue: 49

Pages: 15555-15559

Print publication date: 04/12/2017

Online publication date: 04/10/2017

Acceptance date: 07/09/2017

Date deposited: 11/10/2019

ISSN (print): 1433-7851

ISSN (electronic): 1521-3773

Publisher: Wiley-VCH Verlag GmbH & Co. KGa

URL: https://doi.org/10.1002/anie.201706788

DOI: 10.1002/anie.201706788

PubMed id: 28976073

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