Synthesis of a heterotrifunctional linker for the site-specific preparation of antibody-drug conjugates with two distinct warheads.
Bioorg Med Chem Lett
; 28(23-24): 3617-3621, 2018 12 15.
Article
en En
| MEDLINE
| ID: mdl-30389292
ABSTRACT
Codelivery of multiple therapeutic agents with different anticancer mechanisms can overcome drug resistance as well as generate additive or synergistic anticancer effects that may enhance the antitumor efficacy. Antibody-drug conjugates (ADCs) can be used for highly specific delivery of multiple therapeutic agents with different anticancer mechanisms, though more research is required towards designing flexible platforms on which dual drug ADCs could be prepared. Herein, we describe the synthesis of a heterotrifunctional linker that could be used to construct flexible platforms for preparing dual-cytotoxic drug conjugates in a site-specific manner. As a proof of concept, we synthesized dual drug ADCs carrying monomethyl auristain E (MMAE, tubulin polymerization inhibitor) and pyrrolobenzodiazepine dimer (PBD, DNA minor groove alkylator). We then evaluated the dual drug ADCs for in vitro efficacy and confirmed the dual mechanism of action.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Inmunoconjugados
/
Moduladores de Tubulina
Límite:
Humans
Idioma:
En
Año:
2018
Tipo del documento:
Article