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Lookup NU author(s): Pasquale Morese, Ayaz Ahmad, Dr Mathew MartinORCiD, Dr Richard NobleORCiD, Sara Pintar, Lan Wang, Shangze Xu, Dr Agnieszka Bronowska, Professor Martin NobleORCiD, Dr Hannah Stewart, Professor Mike Waring
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
The discovery of targeted covalent inhibitors is of increasing importance in drug discovery. Finding efficient covalent binders requires modulation of warhead reactivity and optimisation of warhead geometry and non-covalent interactions. Uncoupling the contributions that these factors make to potency is difficult and best practice for a testing cascade that is pragmatic and informative is yet to be fully established. We studied the structure-reactivity-activity relationships of a series of analogues of the EGFR inhibitor poziotinib with point changes in two substructural regions as well as variations in warhead reactivity and geometry. This showed that a simple probe displacement assay that is appropriately tuned in respect of timing and reagent concentrations can reveal structural effects on all three factors: non-covalent affinity, warhead reactivity and geometry. These effects include the detection of potency differences between an enantiomeric pair that differ greatly in their activity and their capacity to form a covalent bond. This difference is rationalised by X-ray crystallography and computational studies and the effect translates quantitatively into cellular mechanistic and phenotypic effects
Author(s): Morese PA, Ahmad A, Martin MP, Noble RA, Pintar S, Wang LZ, Xu S, Lister A, Ward RA, Bronowska A, Noble MEM, Stewart HL, Waring MJ
Publication type: Article
Publication status: Published
Journal: Communications Chemistry
Year: 2025
Volume: 8
Online publication date: 09/04/2025
Acceptance date: 24/03/2025
Date deposited: 10/04/2025
ISSN (electronic): 2399-3669
Publisher: Springer Nature
URL: https://doi.org/10.1038/s42004-025-01501-6
DOI: 10.1038/s42004-025-01501-6
Data Access Statement: Experimental details of compound synthesis and characterisation, protein mass spectrometry analysis computational methods and X-ray crystallography are provided in the Supplementary Information. X-ray crystallographic data are available in the Protein Data Bank (codes: 9FZS for 16 and 9FZR for 17).
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