EGFR-targeted prodrug activation using bioorthogonal alkene-azide click-and-release chemistry
| Autor: | Sarah Hook, Blake Gibson, Júlia C. Camilli, Allan B. Gamble, Jessica M. Fairhall |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Azides
Clinical Biochemistry Pharmaceutical Science Alkenes Biochemistry EGFR Antibody Mice Structure-Activity Relationship In vivo Cell Line Tumor Drug Discovery medicine Animals Humans Prodrugs Doxorubicin Epidermal growth factor receptor Protein Kinase Inhibitors Molecular Biology Cell Proliferation Antibiotics Antineoplastic Dose-Response Relationship Drug Molecular Structure biology Cetuximab Chemistry Organic Chemistry Prodrug In vitro ErbB Receptors Mice Inbred C57BL Cancer research biology.protein Molecular Medicine Female Drug Screening Assays Antitumor Bioorthogonal chemistry medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry. 46:116361 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2021.116361 |
| Popis: | Epidermal growth factor receptor (EGFR) is overexpressed in many cancers and therefore serves as an excellent target for prodrug activation. Functionalised trans-cyclooctenes (TCO) were conjugated to an EGFR antibody (cetuximab), providing a reagent for pre-targeting and localisation of the bioorthogonal reagent. The TCOs react with a 4-azidobenzyl carbamate doxorubicin prodrug via a [3 + 2]-cycloaddition and subsequent self-immolation leads to release of doxorubicin (click-and-release). In vitro cell-based assays demonstrated proof-of-concept, that cetuximab conjugated to highly strained TCO (AB-d-TCO) could bind to the EGFR in a melanoma cell line, and selectively activate the doxorubicin prodrug. In a non-EGFR expressing melanoma cell line, no significant prodrug activation was observed. In vivo experiments using this combination of AB-d-TCO and the azido-doxorubicin prodrug in a murine melanoma model revealed no significant anti-tumour activity or increased survival, suggesting there was insufficient prodrug activation and drug release at the tumour site. |
| Databáze: | OpenAIRE |
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