RESUMEN
Variously substituted indolin-2-ones were synthesized and evaluated for activity against KDR, Flt-1, FGFR-1 and PDGFR. Extension at the 5-position of the oxindole ring with ethyl piperidine (compound 7i) proved to be the most beneficial for attaining both biochemical and cellular potencies. Further optimization of 7i to balance biochemical and cellular potencies with favorable ADME/ PK properties led to the identification of 8h, a compound with a clean CYP profile, acceptable pharmacokinetic and toxicity profiles, and robust efficacy in multiple xenograft tumor models.
Asunto(s)
Diseño de Fármacos , Indoles/síntesis química , Piperidinas/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Animales , Sitios de Unión , Línea Celular Tumoral , Cristalografía por Rayos X , Citocromo P-450 CYP3A/metabolismo , Femenino , Semivida , Humanos , Indoles/farmacocinética , Indoles/uso terapéutico , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Ratones , Neoplasias/tratamiento farmacológico , Piperidinas/farmacocinética , Piperidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Estructura Terciaria de Proteína , Ratas , Proteínas Tirosina Quinasas Receptoras/metabolismo , Relación Estructura-Actividad , Trasplante HeterólogoRESUMEN
CDC7 is a serine/threonine kinase that has been shown to be required for the initiation and maintenance of DNA replication. Up-regulation of CDC7 is detected in multiple tumor cell lines, with inhibition of CDC7 resulting in cell cycle arrest. In this paper, we disclose the discovery of a potent and selective CDC7 inhibitor, XL413 (14), which was advanced into Phase 1 clinical trials. Starting from advanced lead 3, described in a preceding communication, we optimized the CDC7 potency and selectivity to demonstrate in vitro CDC7 dependent cell cycle arrest and in vivo tumor growth inhibition in a Colo-205 xenograft model.
Asunto(s)
Proteínas de Ciclo Celular/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirimidinonas/química , Pirimidinonas/farmacocinética , Animales , Sitios de Unión , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Simulación por Computador , Humanos , Ratones , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Serina-Treonina Quinasas/metabolismo , Estructura Terciaria de Proteína , Pirimidinonas/uso terapéutico , Ratas , Relación Estructura-Actividad , Trasplante Heterólogo , Regulación hacia ArribaRESUMEN
A series of substituted benzofuropyrimidinones with pan-PIM activities and excellent selectivity against a panel of diverse kinases is described. Initial exploration identified aryl benzofuropyrimidinones that were potent, but had cell permeability limitation. Using X-ray crystal structures of the bound PIM-1 complexes with 3, 5m, and 6d, we were able to guide the SAR and identify the alkyl benzofuropyrimidinone (6l) with good PIM potencies, permeability, and oral exposure.