Discovery and characterization of novel allosteric FAK inhibitors.
Eur J Med Chem
; 61: 49-60, 2013 Mar.
Article
en En
| MEDLINE
| ID: mdl-22819505
Focal adhesion kinase (FAK) regulates cell survival and proliferation pathways. Here we report the discovery of a highly selective series of 1,5-dihydropyrazolo[4,3-c][2,1]benzothiazines that demonstrate a novel mode of allosteric inhibition of FAK. These compounds showed slow dissociation from unphosphorylated FAK and were noncompetitive with ATP after long preincubation. Co-crystal structural analysis revealed that the compounds target a novel allosteric site within the C-lobe of the kinase domain, which induces disruption of ATP pocket formation leading to the inhibition of kinase activity. The potency of allosteric inhibition was reduced by phosphorylation of FAK. Coupled SAR analysis revealed that N-substitution of the fused pyrazole is critical to achieve allosteric binding and high selectivity among kinases.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Pirazoles
/
Tiazinas
/
Inhibidores de Proteínas Quinasas
/
Proteína-Tirosina Quinasas de Adhesión Focal
/
Descubrimiento de Drogas
Límite:
Humans
Idioma:
En
Revista:
Eur J Med Chem
Año:
2013
Tipo del documento:
Article
País de afiliación:
Japón
Pais de publicación:
Francia