Synthesis and preclinical evaluation of [
EAI045
EGFR
Epidermal growth factor receptor
TKI
Tyrosine kinase inhibitor
Journal
EJNMMI research
ISSN: 2191-219X
Titre abrégé: EJNMMI Res
Pays: Germany
ID NLM: 101560946
Informations de publication
Date de publication:
16 Feb 2024
16 Feb 2024
Historique:
received:
08
08
2023
accepted:
02
02
2024
medline:
16
2
2024
pubmed:
16
2
2024
entrez:
16
2
2024
Statut:
epublish
Résumé
Mutations in the epidermal growth factor receptor (EGFR) kinase domain are common in non-small cell lung cancer. Conventional tyrosine kinase inhibitors target the mutation site in the ATP binding pocket, thereby inhibiting the receptor's function. However, subsequent treatment resistance mutations in the ATP binding site are common. The EGFR allosteric inhibitor, EAI045, is proposed to have an alternative mechanism of action, disrupting receptor signaling independent of the ATP-binding site. The antibody cetuximab is hypothesized to increase the number of accessible allosteric pockets for EAI045, thus increasing the potency of the inhibitor. This work aimed to gain further knowledge on pharmacokinetics, the EGFR mutation-targeting potential, and the influence of cetuximab on the uptake by radiolabeling EAI045 with carbon-11 and tritium. 2-(5-fluoro-2-hydroxyphenyl)-2-((2-iodobenzyl)amino)-N-(thiazol-2-yl)acetamide and 2-(5-fluoro-2-hydroxyphenyl)-N-(5-iodothiazol-2-yl)-2-(1-oxoisoindolin-2-yl)acetamide were synthesized as precursors for the carbon-11 and tritium labeling of EAI045, respectively. [ EAI045 was successfully labeled with tritium and carbon-11, and the in vivo results indicated [
Sections du résumé
BACKGROUND
BACKGROUND
Mutations in the epidermal growth factor receptor (EGFR) kinase domain are common in non-small cell lung cancer. Conventional tyrosine kinase inhibitors target the mutation site in the ATP binding pocket, thereby inhibiting the receptor's function. However, subsequent treatment resistance mutations in the ATP binding site are common. The EGFR allosteric inhibitor, EAI045, is proposed to have an alternative mechanism of action, disrupting receptor signaling independent of the ATP-binding site. The antibody cetuximab is hypothesized to increase the number of accessible allosteric pockets for EAI045, thus increasing the potency of the inhibitor. This work aimed to gain further knowledge on pharmacokinetics, the EGFR mutation-targeting potential, and the influence of cetuximab on the uptake by radiolabeling EAI045 with carbon-11 and tritium.
RESULTS
RESULTS
2-(5-fluoro-2-hydroxyphenyl)-2-((2-iodobenzyl)amino)-N-(thiazol-2-yl)acetamide and 2-(5-fluoro-2-hydroxyphenyl)-N-(5-iodothiazol-2-yl)-2-(1-oxoisoindolin-2-yl)acetamide were synthesized as precursors for the carbon-11 and tritium labeling of EAI045, respectively. [
CONCLUSIONS
CONCLUSIONS
EAI045 was successfully labeled with tritium and carbon-11, and the in vivo results indicated [
Identifiants
pubmed: 38363422
doi: 10.1186/s13550-024-01078-6
pii: 10.1186/s13550-024-01078-6
doi:
Types de publication
Journal Article
Langues
eng
Pagination
19Subventions
Organisme : H2020 Marie Skłodowska-Curie Actions
ID : 675417
Informations de copyright
© 2024. The Author(s).
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