Discovery of small molecules targeting GRP78 for antiangiogenic and anticancer therapy.
Eur J Med Chem
; 193: 112228, 2020 May 01.
Article
em En
| MEDLINE
| ID: mdl-32199134
ABSTRACT
Glucose Regulated Protein 78 kDa (GRP78) is an attractive antiangiogenic and anticancer target for its selective accumulation on the surface of cancer cells and cancer endothelial cells rather than normal cells. In this study, we identified a novel series of small molecules that binds to GRP78, exhibiting potent antiangiogenic and anticancer activities without affecting normal cells. Among these, FL5,2-(4-((4-acetamidophenoxy)methyl)phenyl)-N-isobutylbenzofuran-3-carboxamide, was superior to others due to its strong binding affinity to GRP78 (an increase in the Tm > 2 °C stabilising the GRP78 protein) and potent antiangiogenic and anticancer activities against human umbilical vein endothelial cells (HUVEC) (EC50 = 1.514 µM) and human renal cancer cells (786-O) (50% cell death at 10 µM). Furthermore, FL5 displayed no cytotoxic activity towards mouse fibroblast cells (Swiss-3T3), which do not harbour cell surface GRP78 under normal condition. FL5 was less detrimental to ATPase activity, which is essential for normal cells, as seen in the virtual docking studies. This study reports the discovery of novel small molecules targeting GRP78 with potent antiangiogenic and anticancer activities and less toxicity to normal cells, which provides prototype candidates for novel paths for cancer therapy.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Inibidores da Angiogênese
/
Bibliotecas de Moléculas Pequenas
/
Descoberta de Drogas
/
Proteínas de Choque Térmico
/
Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article