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The Meisenheimer Complex as a Paradigm in Drug Discovery: Reversible Covalent Inhibition through C67 of the ATP Binding Site of PLK1

Pearson, Russell J.; Blake, David G.; Mezna, Mokdad; Fischer, Peter M.; Westwood, Nicholas J.; McInnes, Campbell

The Meisenheimer Complex as a Paradigm in Drug Discovery: Reversible Covalent Inhibition through C67 of the ATP Binding Site of PLK1 Thumbnail


Authors

Russell J. Pearson

David G. Blake

Mokdad Mezna

Peter M. Fischer

Nicholas J. Westwood

Campbell McInnes



Abstract

The polo kinase family are important oncology targets that act in regulating entry into and progression through mitosis. Structure-guided discovery of a new class of inhibitors of Polo-like kinase 1 (PLK1) catalytic activity that interact with Cys67 of the ATP binding site is described. Compounds containing the benzothiazole N-oxide scaffold not only bind covalently to this residue, but are reversible inhibitors through the formation of Meisenheimer complexes. This mechanism of kinase inhibition results in compounds that can target PLK1 with high selectivity, while avoiding issues with irreversible covalent binding and interaction with other thiol-containing molecules in the cell. Due to renewed interest in covalent drugs and the plethora of potential drug targets, these represent prototypes for the design of kinase inhibitory compounds that achieve high specificity through covalent interaction and yet still bind reversibly to the ATP cleft, a strategy that could be applied to avoid issues with conventional covalent binders.

Citation

Pearson, R. J., Blake, D. G., Mezna, M., Fischer, P. M., Westwood, N. J., & McInnes, C. (2018). The Meisenheimer Complex as a Paradigm in Drug Discovery: Reversible Covalent Inhibition through C67 of the ATP Binding Site of PLK1. Cell Chemical Biology, 25(9), 1107-1116.e4. https://doi.org/10.1016/j.chembiol.2018.06.001

Journal Article Type Article
Acceptance Date May 31, 2018
Online Publication Date Jul 12, 2018
Publication Date Sep 20, 2018
Deposit Date Jul 30, 2018
Publicly Available Date Mar 29, 2024
Journal Cell Chemical Biology
Electronic ISSN 2451-9448
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 25
Issue 9
Pages 1107-1116.e4
DOI https://doi.org/10.1016/j.chembiol.2018.06.001
Keywords Kinase; inhibitor; Polo-like kinase; Meisenheimer complex; oncology; cancer; covalent inhibition
Public URL https://nottingham-repository.worktribe.com/output/853356
Publisher URL https://www.sciencedirect.com/science/article/pii/S2451945618301910?via%3Dihub
Additional Information This article is maintained by: Elsevier; Article Title: The Meisenheimer Complex as a Paradigm in Drug Discovery: Reversible Covalent Inhibition through C67 of the ATP Binding Site of PLK1; Journal Title: Cell Chemical Biology; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.chembiol.2018.06.001; Content Type: article; Copyright: © 2018 Elsevier Ltd.

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