Uncialamycin as a novel payload for antibody drug conjugate (ADC) based targeted cancer therapy.
Bioorg Med Chem Lett
; 29(3): 466-470, 2019 02 01.
Article
em En
| MEDLINE
| ID: mdl-30579797
ABSTRACT
Uncialamycin analogs were evaluated as potential cytotoxic agents in an antibody-drug conjugate (ADC) approach to treating human cancer. These analogs were synthesized using Hauser annulations of substituted phthalides as a key step. A highly potent uncialamycin analog 3c with a valine-citrulline dipeptide linker was conjugated to an anti-mesothelin monoclonal antibody (mAb) through lysines to generate a meso-13 conjugate. This conjugate demonstrated subnanomolar potency (IC50â¯=â¯0.88â¯nM, H226 cell line) in in vitro cytotoxicity experiments with good immunological specificity to mesothelin-positive lung cancer cell lines. The potency and mechanism of action of this uncialamycin class of enediyne antitumor antibiotics make them attractive payloads in ADC-based cancer therapy.
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Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Antraquinonas
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Imunoconjugados
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Neoplasias Pulmonares
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Anticorpos Monoclonais
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Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
Bioorg Med Chem Lett
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2019
Tipo de documento:
Article