Pearson, RJ, Blake, DG, Mezna, M, Fischer, PM, Westwood, NJ and 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). pp. 1107-1116. ISSN 2451-9456

[thumbnail of ~$180727_Pearson CellChemical Biology 2018.docx] Text
~$180727_Pearson CellChemical Biology 2018.docx - Accepted Version
Available under License Creative Commons Attribution Non-commercial No Derivatives.

Download (162B)


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.

Item Type: Article
Additional Information: This is the accepted author manuscript (AAM). The final published version (version of record) is available online via Elsevier at - please refer to any applicable terms of use of the publisher.
Uncontrolled Keywords: kinase, inhibitor, Polo-like kinase, Meisenheimer complex, oncology, cancer, covalent inhibition
Subjects: R Medicine > RS Pharmacy and materia medica
Divisions: Faculty of Medicine and Health Sciences > School of Pharmacy
Related URLs:
Depositing User: Symplectic
Date Deposited: 27 Jul 2018 09:59
Last Modified: 12 Jul 2019 01:30

Actions (login required)

View Item
View Item