RESUMEN
The C797S mutation is one of the major factors behind resistance to the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Herein, we describe the discovery of DS06652923, a novel, potent, and orally available EGFR-triple-mutant inhibitor. Through scaffold hopping from the previously reported nicotinamide derivative, a novel biaryl scaffold was obtained. The potency was successfully enhanced by the introduction of basic substituents based on analysis of the docking study results. In addition, the difluoromethoxy group on the pyrazole ring improved the kinase selectivity by inducing steric clash with the other kinases. The most optimized compound, DS06652923, achieved tumor regression in the Ba/F3 allograft model upon its oral administration.
Asunto(s)
Antineoplásicos , Receptores ErbB , Mutación , Inhibidores de Proteínas Quinasas , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Receptores ErbB/genética , Antineoplásicos/química , Antineoplásicos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/síntesis química , Humanos , Administración Oral , Animales , Relación Estructura-Actividad , Ratones , Descubrimiento de Drogas , Simulación del Acoplamiento Molecular , Estructura Molecular , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Proliferación Celular/efectos de los fármacosRESUMEN
R-268712 is a novel and specific inhibitor of activin receptor-like kinase 5 (ALK5), a transforming growth factor ß (TGF-ß) type I receptor. Evaluation of in vitro inhibition indicated that R-268712 is a potent and selective inhibitor of ALK5 with an IC50 of 2.5nM, an approximately 5000-fold more selectivity for ALK5 than p38 mitogen-activated protein kinase (MAPK). Oral administration of R-268712 at doses of 1, 3 and 10mg/kg also inhibited the development of renal fibrosis in a dose-dependent manner in a unilateral ureteral obstruction (UUO) model. Additionally, we evaluated the efficacy of R-268712 in a heminephrectomized anti-Thy1 glomerulonephritis model at doses of 0.3 and 1mg/kg. R-268712 reduced proteinuria and glomerulosclerosis significantly with improvement of renal function. Collectively, these results suggested that R-268712 and other ALK5 inhibitors could suppress glomerulonephritis as well as glomerulosclerosis by an inhibitory mechanism that involves suppression of TGF-ß signaling.