Structure- and Reactivity-Based Development of Covalent Inhibitors of the Activating and Gatekeeper Mutant Forms of the Epidermal Growth Factor Receptor (EGFR)

Ward, Richard A.; Anderton, Mark J.; Ashton, Susan; Bethel, Paul A.; Box, Matthew; Butterworth, Sam; Colclough, Nicola; Chorley, Christopher G.; Chuaqui, Claudio; Cross, Darren A. E.; Dakin, Les A.; Debreczeni, Judit É.; Eberlein, Cath; Finlay, M. Raymond V.; Hill, George B.; Grist, Matthew; Klinowska, Teresa C. M.; Lane, Clare; Martin, Scott; Orme, Jonathon P.; Smith, Peter; Wang, Fengjiang; Waring, Michael J.

doi:10.1021/jm400822z

Cited by 279Lung Cancer Treatments and MutationsHER2/EGFR in Cancer ResearchSynthesis and biological activity

Structure- and Reactivity-Based Development of Covalent Inhibitors of the Activating and Gatekeeper Mutant Forms of the Epidermal Growth Factor Receptor (EGFR)

Ward, Richard A., Anderton, Mark J., Ashton, Susan, Bethel, Paul A., Box, Matthew, Butterworth, Sam, Colclough, Nicola, Chorley, Christopher G. +15 more·2013·Journal of Medicinal Chemistry

DOI 10.1021/jm400822z

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Abstract

A novel series of small-molecule inhibitors has been developed to target the double mutant form of the epidermal growth factor receptor (EGFR) tyrosine kinase, which is resistant to treatment with gefitinib and erlotinib. Our reported compounds also show selectivity over wild-type EGFR. Guided by molecular modeling, this series was evolved to target a cysteine residue in the ATP binding site via covalent bond formation and demonstrates high levels of activity in cellular models of the double mutant form of EGFR. In addition, these compounds show significant activity against the activating mutations, which gefitinib and erlotinib target and inhibition of which gives rise to their observed clinical efficacy. A glutathione (GSH)-based assay was used to measure thiol reactivity toward the electrophilic functionality of the inhibitor series, enabling both the identification of a suitable reactivity window for their potency and the development of a reactivity quantitative structure-property relationship (QSPR) to support design.

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Authors: Ward, R. A., Anderton, M. J., Ashton, S., Bethel, P. A., Box, M., Butterworth, S., Colclough, N., Chorley, C. G., Chuaqui, C., Cross, D. A. E., Dakin, L. A., Debreczeni, J. É., Eberlein, C., Finlay, M. R. V., Hill, G. B., Grist, M., Klinowska, T. C. M., Lane, C., Martin, S., Orme, J. P., Smith, P., Wang, F., & Waring, M. J.
Affiliations: AstraZeneca (United Kingdom) (GB)
AstraZeneca (United States) (US)
Corresponding author: Ward, Richard A.
ORCID: Ward, Richard A.
Box, Matthew
Butterworth, Sam
Cross, Darren A. E.
Eberlein, Cath
Finlay, M. Raymond V.
Klinowska, Teresa C. M.
Smith, Peter
Wang, Fengjiang
Venue: Journal of Medicinal Chemistry
Publisher: American Chemical Society (ACS)
Published: 2013-08-30
Volume: 56
Issue: 17
Pages: 7025-7048
ISSN: 0022-2623 (ISSN-L)
1520-4804
DOI: 10.1021/jm400822z
OpenAlex: W1963826141
Cited by: 279
References: 42
Citations by year: 2026: 17 · 2025: 36 · 2024: 27 · 2023: 22 · 2022: 24 · 2021: 22 · 2020: 21 · 2019: 19 · 2018: 27 · 2017: 17 · 2016: 22 · 2015: 16 · 2014: 9
FWCI: 14.36
Type: journal article
Language: en
Open access: closed
Locations: Journal of Medicinal Chemistry (publishedVersion)
PubMed (publishedVersion)
Research Explorer (The University of Manchester) (publishedVersion)
DORA PSI (Paul Scherrer Institute) (submittedVersion)
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
Keywords: epidermal growth factor receptor, EGFR tyrosine kinase inhibitors, covalent inhibitors, activating mutations, gatekeeper mutation, gefitinib resistance, erlotinib resistance, ATP binding site, QSPR, small molecule inhibitors
MeSH terms: Models, Molecular, Mutation, Structure-Activity Relationship, ErbB Receptors

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Structure- and Reactivity-Based Development of Covalent Inhibitors of the Activating and Gatekeeper Mutant Forms of the Epidermal Growth Factor Receptor (EGFR)

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