Covalent inhibition of epidermal growth factor receptor using a long-lived iridium(III)-afatinib probe.
Int J Biol Macromol
; 259(Pt 1): 129211, 2024 Feb.
Article
em En
| MEDLINE
| ID: mdl-38184034
ABSTRACT
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.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Carcinoma de Células Escamosas
/
Neoplasias Pulmonares
Limite:
Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article