Late-Stage Desulfurization Enables Rapid and Efficient Solid-Phase Synthesis of Cathepsin-Cleavable Linkers for Antibody-Drug Conjugates.
Bioconjug Chem
; 35(7): 1007-1014, 2024 Jul 17.
Article
en En
| MEDLINE
| ID: mdl-38874557
ABSTRACT
The synthesis of linker-payloads is a critical step in developing antibody-drug conjugates (ADCs), a rapidly advancing therapeutic approach in oncology. The conventional method for synthesizing cathepsin B-labile dipeptide linkers, which are commonly used in ADC development, involves the solution-phase assembly of cathepsin B-sensitive dipeptides, followed by the installation of self-immolative para-aminobenzyl carbonate to facilitate the attachment of potent cytotoxic payloads. However, this approach is often low yield and laborious, especially when extending the peptide chain with components like glutamic acid to improve mouse serum stability or charged amino acids or poly(ethylene glycol) moieties to enhance linker hydrophilicity. Here, we introduce a novel approach utilizing late-stage desulfurization chemistry, enabling safe, facile, and cost-effective access to the cathepsin B-cleavable linker, Val-Ala-PABC-MMAE, on resin for the first time.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Oligopéptidos
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Catepsina B
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Inmunoconjugados
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Técnicas de Síntesis en Fase Sólida
Límite:
Animals
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Humans
Idioma:
En
Año:
2024
Tipo del documento:
Article