Design, synthesis and evaluation of novel, potent DNA alkylating agents and their antibody-drug conjugates (ADCs).
Bioorg Med Chem Lett
; 29(17): 2455-2458, 2019 09 01.
Article
em En
| MEDLINE
| ID: mdl-31350125
ABSTRACT
Antibody-drug conjugates (ADCs) incorporating potent indolinobenzodiazepine (IGN) DNA alkylators as the cytotoxic payload are currently undergoing clinical evaluation. The optimized design of these payloads consists of an unsymmetrical dimer possessing both an imine and an amine effectively eliminating DNA crosslinking and demonstrating improved tolerability in mice. Here we present an alternate approach to generating DNA alkylating ADCs by linking the IGN monomer with a biaryl system which has a high DNA binding affinity to potentially enhance tolerability. These BIA ADCs were found to be highly cytotoxic in vitro and demonstrated potent antitumor activity in vivo.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Desenho de Fármacos
/
Imunoconjugados
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Alquilantes
Limite:
Animals
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Humans
Idioma:
En
Revista:
Bioorg Med Chem Lett
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Estados Unidos