EGFR-targeted prodrug activation using bioorthogonal alkene-azide click-and-release chemistry. (15th September 2021)

• Record Type: Journal Article
• Authors: Fairhall, Jessica M.; Camilli, Júlia C.; Gibson, Blake H.; Hook, Sarah; Gamble, Allan B.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 46(2021)
• Publication Date: 2021-09-15
• Subjects: Bioorthogonal Chemistry -- Click-and-release Strategies -- Prodrug activation -- Cancer cell targeting; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2021.116361
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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.