Discovery of a simplified deguelin analog as an HSP90 C-terminal inhibitor for HER2-positive breast cancer.
Bioorg Med Chem Lett
; 45: 128134, 2021 08 01.
Article
en En
| MEDLINE
| ID: mdl-34044120
ABSTRACT
A series of O-substituted analogs of the C-ring-truncated scaffold of deguelin designed as heat shock protein 90 (HSP90) C-terminal inhibitors were investigated as novel antitumor agents against human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Among the synthesized compounds, compound 37 displayed significant inhibition in both trastuzumab-sensitive and trastuzumab-resistant breast cancer cells with little cytotoxicity to normal cells. Mechanistic studies of compound 37 carried out by HSP90α C-terminal inhibitor screening, the induction of the heat shock response and downregulation of HSP90 client proteins indicated that the antitumor activity of 37 in breast cancer cells could be attributed to the destabilization and inactivation of HSP90 client proteins by the binding of 37 to the C-terminal domain of HSP90. A molecular docking study of compound 37 with a HSP90 homology model indicated that its S-isomer fit well in the ATP binding site of the C-terminal domain, forming key interactions.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Rotenona
/
Neoplasias de la Mama
/
Proteínas HSP90 de Choque Térmico
/
Descubrimiento de Drogas
/
Antineoplásicos
Tipo de estudio:
Prognostic_studies
Límite:
Female
/
Humans
Idioma:
En
Revista:
Bioorg Med Chem Lett
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2021
Tipo del documento:
Article