A Guanidyl-Based Bivalent Peptidomimetic Inhibits K-Ras Prenylation and Association with c-Raf.
Chemistry
; 25(59): 13531-13536, 2019 Oct 22.
Article
em En
| MEDLINE
| ID: mdl-31393030
ABSTRACT
Unusual lipid modification of K-Ras makes Ras-directed cancer therapy a challenging task. Aiming to disrupt electrostatic-driven protein-protein interactions (PPIs) of K-Ras with FTase and GGTaseâ
I, a series of bivalent dual inhibitors that recognize the active pocket and the common acidic surface of FTase and GGTaseâ
I were designed. The structure-activity-relationship study resulted in 8 b, in which a biphenyl-based peptidomimetic FTI-277 was attached to a guanidyl-containing gallate moiety through an alkyl linker. Cell-based evaluation demonstrated that 8 b exhibited substantial inhibition of K-Ras processing without apparent interference with Rap-1A processing. Fluorescent imaging showed that 8 b disrupts localization of K-Ras to the plasma membrane and impairs interaction with c-Raf, whereas only FTI-277 was found to be inactive. These results suggest that targeting the PPI interface of K-Ras may provide an alternative method of inhibiting K-Ras.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Serina-Treonina Quinases
/
Proteínas ras
/
Inibidores Enzimáticos
/
Metionina
Tipo de estudo:
Risk_factors_studies
Idioma:
En
Revista:
Chemistry
Assunto da revista:
QUIMICA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Japão