Covalent inhibition of epidermal growth factor receptor using a long-lived iridium(III)-afatinib probe
Copyright © 2024 Elsevier B.V. All rights reserved..
The overexpression and overactivation of epidermal growth factor receptor (EGFR) are frequently observed in human cancers, including squamous cell carcinoma and adenocarcinoma. In this study, a covalent EGFR probe was developed by conjugating afatinib to an iridium(III) scaffold. Complex 1 showed enhanced luminescence in living epidermoid squamous carcinoma A431 cells compared to other cell lines, via engaging EGFR as confirmed via CETSA and knockdown experiments. Moreover, complex 1 inhibited downstream targets of EGFR in cellulo with repression persisting after removal of the complex, indicating an irreversible mode of inhibition. Finally, complex 1 showed potent antiproliferative activity against A431 cells with comparable potency to afatinib alone. To our knowledge, complex 1 is the first EGFR covalent inhibitor based on an iridium scaffold reported in the literature, with the potential to be further explored as a theranostic agent in the future.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:259 |
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| Enthalten in: |
International journal of biological macromolecules - 259(2024), Pt 1 vom: 01. Feb., Seite 129211 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Nao, Sang-Cuo [VerfasserIn] |
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| Links: |
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| Themen: |
41UD74L59M |
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| Anmerkungen: |
Date Completed 22.02.2024 Date Revised 22.02.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ijbiomac.2024.129211 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
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| 520 | |a The overexpression and overactivation of epidermal growth factor receptor (EGFR) are frequently observed in human cancers, including squamous cell carcinoma and adenocarcinoma. In this study, a covalent EGFR probe was developed by conjugating afatinib to an iridium(III) scaffold. Complex 1 showed enhanced luminescence in living epidermoid squamous carcinoma A431 cells compared to other cell lines, via engaging EGFR as confirmed via CETSA and knockdown experiments. Moreover, complex 1 inhibited downstream targets of EGFR in cellulo with repression persisting after removal of the complex, indicating an irreversible mode of inhibition. Finally, complex 1 showed potent antiproliferative activity against A431 cells with comparable potency to afatinib alone. To our knowledge, complex 1 is the first EGFR covalent inhibitor based on an iridium scaffold reported in the literature, with the potential to be further explored as a theranostic agent in the future | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a Covalent inhibitor | |
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| 650 | 7 | |a Protein Kinase Inhibitors |2 NLM | |
| 700 | 1 | |a Kong, Lingtan |e verfasserin |4 aut | |
| 700 | 1 | |a Chan, Daniel Shiu-Hin |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Jianhua |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Le-Sheng |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Lei |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Jia |e verfasserin |4 aut | |
| 700 | 1 | |a Wong, Chun-Yuen |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Wanhe |e verfasserin |4 aut | |
| 700 | 1 | |a Leung, Chung-Hang |e verfasserin |4 aut | |
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