RESUMEN
The histone chaperone anti-silencing function 1 (Asf1) has emerged as a promising target for therapeutic intervention for multiple cancers (Cell2006, 127, 458). Asf1 is involved in the packaging of the eukaryotic genome into chromatin, which is essential for normal growth, development, and differentiation, as this regulates all nuclear processes that use DNA as a substrate. Starting from a collection of HTS leads, we identified a series of N-acyl hydrazones as novel inhibitors of the Asf-histone H3/H4 interaction. These compounds represent the first example of inhibitors capable of disrupting the Asf1-H3/H4 complex.
Asunto(s)
Proteínas de Ciclo Celular/antagonistas & inhibidores , Histonas/antagonistas & inhibidores , Humanos , Chaperonas MolecularesRESUMEN
Virtual and high-throughput screening identified imidazo[1,2-a]pyrazines as inhibitors of B-Raf. We describe the rationale, SAR, and evolution of the initial hits to a series of furo[2,3-c]pyridine indanone oximes as highly potent and selective inhibitors of B-Raf.
Asunto(s)
Indanos/química , Oximas/química , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Piridinas/química , Animales , Sitios de Unión , Línea Celular Tumoral , Simulación por Computador , Evaluación Preclínica de Medicamentos , Humanos , Indanos/síntesis química , Indanos/farmacocinética , Microsomas Hepáticos/metabolismo , Modelos Químicos , Modelos Moleculares , Oximas/síntesis química , Oximas/farmacocinética , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
The development of inhibitors of B-Raf(V600E) serine-threonine kinase is described. Various head-groups were examined to optimize inhibitor activity and ADME properties. Several of the head-groups explored, including naphthol, phenol and hydroxyamidine, possessed good activity but had poor pharmacokinetic exposure in mice. Exposure was improved by incorporating more metabolically stable groups such as indazole and tricyclic pyrazole, while indazole could also be optimized for good cellular activity.