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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

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Pearson_2018_CCB_MeisenheimerComplex_AAM.pdf (1.179Mb)
Date
12/07/2018
Author
Pearson, Russell J.
Blake, David G.
Mezna, Mokdad
Fischer, Peter M.
Westwood, Nicholas J.
McInnes, Campbell
Keywords
Kinase
Inhibitor
Polo-like kinase
Meisenheimer complex
Oncology
Cancer
Covalent inhibition
QD Chemistry
RM Therapeutics. Pharmacology
NDAS
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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 , vol. In press . https://doi.org/10.1016/j.chembiol.2018.06.001
Publication
Cell Chemical Biology
Status
Peer reviewed
DOI
https://doi.org/10.1016/j.chembiol.2018.06.001
ISSN
2451-9456
Type
Journal article
Rights
© 2018 Elsevier Ltd. This work has been made available online in accordance with the publisher’s policies. This is the author created, accepted version manuscript following peer review and may differ slightly from the final published version. The final published version of this work is available at: https://doi.org/10.1016/j.chembiol.2018.06.001
Description
The authors would like to thank many at Cyclacel who contributed to this project and also especially acknowledge the Scottish Executive for provision of funding through a SCORE award.
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  • University of St Andrews Research
URI
http://hdl.handle.net/10023/18089

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