Factors affecting irreversible inhibition of EGFR and influence of chirality on covalent binding
Abstract 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...
Saved in:
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-04-01
|
| Series: | Communications Chemistry |
| Online Access: | https://doi.org/10.1038/s42004-025-01501-6 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849731910523158528 |
|---|---|
| author | Pasquale A. Morese Ayaz Ahmad Mathew P. Martin Richard A. Noble Sara Pintar Lan Z. Wang Shangze Xu Andrew Lister Richard A. Ward Agnieszka K. Bronowska Martin E. M. Noble Hannah L. Stewart Michael J. Waring |
| author_facet | Pasquale A. Morese Ayaz Ahmad Mathew P. Martin Richard A. Noble Sara Pintar Lan Z. Wang Shangze Xu Andrew Lister Richard A. Ward Agnieszka K. Bronowska Martin E. M. Noble Hannah L. Stewart Michael J. Waring |
| author_sort | Pasquale A. Morese |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-0f4e344ee95c402b81446b50b5a0be32 |
| institution | DOAJ |
| issn | 2399-3669 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Chemistry |
| spelling | doaj-art-0f4e344ee95c402b81446b50b5a0be322025-08-20T03:08:24ZengNature PortfolioCommunications Chemistry2399-36692025-04-01811810.1038/s42004-025-01501-6Factors affecting irreversible inhibition of EGFR and influence of chirality on covalent bindingPasquale A. Morese0Ayaz Ahmad1Mathew P. Martin2Richard A. Noble3Sara Pintar4Lan Z. Wang5Shangze Xu6Andrew Lister7Richard A. Ward8Agnieszka K. Bronowska9Martin E. M. Noble10Hannah L. Stewart11Michael J. Waring12Cancer Research Horizons Newcastle Drug Discovery Unit, Chemistry, School of Natural and Environmental Sciences, Bedson Building, Newcastle UniversityChemistry, School of Natural and Environmental Sciences, Bedson Building, Newcastle UniversityCancer Research Horizons Newcastle Drug Discovery Unit, Translational and Clinical Research Institute, Paul O’Gorman Building, Newcastle UniversityCancer Research Horizons Newcastle Drug Discovery Unit, Translational and Clinical Research Institute, Paul O’Gorman Building, Newcastle UniversityCancer Research Horizons Newcastle Drug Discovery Unit, Translational and Clinical Research Institute, Paul O’Gorman Building, Newcastle UniversityCancer Research Horizons Newcastle Drug Discovery Unit, Translational and Clinical Research Institute, Paul O’Gorman Building, Newcastle UniversityChemistry, School of Natural and Environmental Sciences, Bedson Building, Newcastle UniversityOncology iMed, R&D, AstraZenecaOncology iMed, R&D, AstraZenecaChemistry, School of Natural and Environmental Sciences, Bedson Building, Newcastle UniversityCancer Research Horizons Newcastle Drug Discovery Unit, Translational and Clinical Research Institute, Paul O’Gorman Building, Newcastle UniversityCancer Research Horizons Newcastle Drug Discovery Unit, Chemistry, School of Natural and Environmental Sciences, Bedson Building, Newcastle UniversityCancer Research Horizons Newcastle Drug Discovery Unit, Chemistry, School of Natural and Environmental Sciences, Bedson Building, Newcastle UniversityAbstract 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.https://doi.org/10.1038/s42004-025-01501-6 |
| spellingShingle | Pasquale A. Morese Ayaz Ahmad Mathew P. Martin Richard A. Noble Sara Pintar Lan Z. Wang Shangze Xu Andrew Lister Richard A. Ward Agnieszka K. Bronowska Martin E. M. Noble Hannah L. Stewart Michael J. Waring Factors affecting irreversible inhibition of EGFR and influence of chirality on covalent binding Communications Chemistry |
| title | Factors affecting irreversible inhibition of EGFR and influence of chirality on covalent binding |
| title_full | Factors affecting irreversible inhibition of EGFR and influence of chirality on covalent binding |
| title_fullStr | Factors affecting irreversible inhibition of EGFR and influence of chirality on covalent binding |
| title_full_unstemmed | Factors affecting irreversible inhibition of EGFR and influence of chirality on covalent binding |
| title_short | Factors affecting irreversible inhibition of EGFR and influence of chirality on covalent binding |
| title_sort | factors affecting irreversible inhibition of egfr and influence of chirality on covalent binding |
| url | https://doi.org/10.1038/s42004-025-01501-6 |
| work_keys_str_mv | AT pasqualeamorese factorsaffectingirreversibleinhibitionofegfrandinfluenceofchiralityoncovalentbinding AT ayazahmad factorsaffectingirreversibleinhibitionofegfrandinfluenceofchiralityoncovalentbinding AT mathewpmartin factorsaffectingirreversibleinhibitionofegfrandinfluenceofchiralityoncovalentbinding AT richardanoble factorsaffectingirreversibleinhibitionofegfrandinfluenceofchiralityoncovalentbinding AT sarapintar factorsaffectingirreversibleinhibitionofegfrandinfluenceofchiralityoncovalentbinding AT lanzwang factorsaffectingirreversibleinhibitionofegfrandinfluenceofchiralityoncovalentbinding AT shangzexu factorsaffectingirreversibleinhibitionofegfrandinfluenceofchiralityoncovalentbinding AT andrewlister factorsaffectingirreversibleinhibitionofegfrandinfluenceofchiralityoncovalentbinding AT richardaward factorsaffectingirreversibleinhibitionofegfrandinfluenceofchiralityoncovalentbinding AT agnieszkakbronowska factorsaffectingirreversibleinhibitionofegfrandinfluenceofchiralityoncovalentbinding AT martinemnoble factorsaffectingirreversibleinhibitionofegfrandinfluenceofchiralityoncovalentbinding AT hannahlstewart factorsaffectingirreversibleinhibitionofegfrandinfluenceofchiralityoncovalentbinding AT michaeljwaring factorsaffectingirreversibleinhibitionofegfrandinfluenceofchiralityoncovalentbinding |