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Investigations on Small Molecule Inhibitors Targeting the Histone H3K4 tri-methyllysine Binding PHD-finger of JmjC Histone Demethylases

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posted on 2018-05-22, 10:39 authored by Bhaskar Bhushan, Alexandre Erdmann, Yijia Zhang, Roman Belle, Catrine Johannson, Udo Oppermann, Richard J. Hopkinson, Christopher J. Schofield, Akane Kawamura
Plant homeodomain (PHD) containing proteins are important epigenetic regulators and are of interest as potential drug targets. Inspired by the amiodarone derivatives reported to inhibit the PHD finger 3 of KDM5A (KDM5A(PHD3)), a set of compounds were synthesised. Amiodarone and its derivatives were observed to weakly disrupt the interactions of a histone H3K4me3 peptide with KDM5A(PHD3). Selected amiodarone derivatives inhibited catalysis of KDM5A, but in a PHD-finger independent manner. Amiodarone derivatives also bind to H3K4me3-binding PHD-fingers from the KDM7 subfamily. Further work is required to develop potent and selective PHD finger inhibitors.

Funding

This work was supported by the European Research Council Starting Grant [679479], Cancer Research UK Programme Grant [C8717/A18245, AK, CJS] and project grant to UO, the Wellcome Trust [203141/Z/16/Z], British Heart Foundation Centre for Research Excellence Oxford [RE/13/1/30181], Arthritis Research UK [program grant 20522], Leducq Foundation, Rosetrees Trust, the Engineering and Physical Science Research Council, Foundation ARC (Fellowship to AE), and the Royal Society Dorothy Hodgkin Fellowship [DH120028 to AK]. RJH acknowledges a William R. Miller Junior Research Fellowship, St. Edmund Hall, Oxford.

History

Citation

Bioorganic and Medicinal Chemistry, 2018

Author affiliation

/Organisation/COLLEGE OF SCIENCE AND ENGINEERING/Department of Chemistry

Version

  • VoR (Version of Record)

Published in

Bioorganic and Medicinal Chemistry

Publisher

Elsevier

issn

0968-0896

eissn

1464-3391

Acceptance date

2018-03-18

Copyright date

2018

Available date

2018-05-22

Publisher version

https://www.sciencedirect.com/science/article/pii/S096808961830347X?via=ihub

Notes

Supplementary data associated with this article can be found, inthe online version, at https://doi.org/10.1016/j.bmc.2018.03.030

Language

en

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