RESUMEN
Inhibition of cyclin-dependent kinases (CDKs) has emerged as an attractive strategy for the development of novel oncology therapeutics. Herein is described the utilization of an in vivo screening approach with integrated efficacy and tolerability parameters to identify candidate CDK inhibitors with a suitable balance of activity and tolerability. This approach has resulted in the identification of SCH 727965, a potent and selective CDK inhibitor that is currently undergoing clinical evaluation.
RESUMEN
Experimental autoimmune uveitis (EAU) represents autoimmune uveitis in humans. We examined the role of the interleukin (IL)-23-IL-17 and IL-12-T helper cell (Th)1 pathways in the pathogenesis of EAU. IL-23 but not IL-12 was necessary to elicit disease by immunization with the retinal antigen (Ag) interphotoreceptor retinoid-binding protein (IRBP) in complete Freund's adjuvant. IL-17 played a dominant role in this model; its neutralization prevented or reversed disease, and Th17 effector cells induced EAU in the absence of interferon (IFN)-gamma. In a transfer model, however, a polarized Th1 line could induce severe EAU independently of host IL-17. Furthermore, induction of EAU with IRBP-pulsed mature dendritic cells required generation of an IFN-gamma-producing effector response, and an IL-17 response by itself was insufficient to elicit pathology. Finally, genetic deficiency of IL-17 did not abrogate EAU susceptibility. Thus, autoimmune pathology can develop in the context of either a Th17 or a Th1 effector response depending on the model. The data suggest that the dominant effector phenotype may be determined at least in part by conditions present during initial exposure to Ag, including the quality/quantity of Toll-like receptor stimulation and/or type of Ag-presenting cells. These data also raise the possibility that the nonredundant requirement for IL-23 in EAU may extend beyond its role in promoting the Th17 effector response and help provide a balance in the current Th1 versus Th17 paradigm.
Asunto(s)
Enfermedades Autoinmunes/enzimología , Enfermedades Autoinmunes/patología , Autoinmunidad/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Células TH1/inmunología , Animales , Antígenos/inmunología , Enfermedades Autoinmunes/prevención & control , Línea Celular , Células Dendríticas/inmunología , Susceptibilidad a Enfermedades , Ojo/patología , Humanos , Mediadores de Inflamación/metabolismo , Interferón gamma/deficiencia , Interferón gamma/inmunología , Subunidad p35 de la Interleucina-12/deficiencia , Subunidad p35 de la Interleucina-12/inmunología , Interleucina-17/inmunología , Interleucina-23/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Inmunológicos , Pruebas de Neutralización , Regulación hacia Arriba , Uveítis/inmunología , Uveítis/prevención & controlRESUMEN
A series of four bicyclic cores were prepared and evaluated as cyclin-dependent kinase-2 (CDK2) inhibitors. From the in-vitro and cell-based analysis, the pyrazolo[1,5-a]pyrimidine core (represented by 9) emerged as the superior core for further elaboration in the identification of novel CDK2 inhibitors.
Asunto(s)
Quinasa 2 Dependiente de la Ciclina/efectos de los fármacos , Proteínas Inhibidoras de las Quinasas Dependientes de la Ciclina/química , Proteínas Inhibidoras de las Quinasas Dependientes de la Ciclina/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/química , Pirazoles/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Sitios de Unión , Cristalografía por Rayos X , Quinasa 2 Dependiente de la Ciclina/química , Proteínas Inhibidoras de las Quinasas Dependientes de la Ciclina/síntesis química , Diseño de Fármacos , Concentración 50 Inhibidora , Estructura Molecular , Unión Proteica , Inhibidores de Proteínas Quinasas/síntesis química , Pirazoles/síntesis química , Pirimidinas/síntesis químicaRESUMEN
Properly substituted pyrazolo[1,5-a]pyrimidines are potent and selective CDK2 inhibitors. Compound 15j is orally available and showed efficacy in a mouse A2780 xenograft model.