RESUMEN
A series of 2-aminothiadiazole of inhibitors of AKT1 is described. SAR relationships are discussed, along with selectivity for protein kinase A (PKA) and cyclin-dependent kinase 2 (CDK2). Moderate selectivity observed in several compounds for AKT1 versus PKA is rationalized by X-ray crystallographic analysis. Key compounds showed activity in cellular assays measuring phosphorylation of two AKT substrates, PRAS40 and FKHRL1. Compound 30 was advanced to a mouse liver PD assay, where it showed dose-dependent inhibition of AKT activity, as measured by the inhibition of phospho-PRAS40.
Asunto(s)
Antineoplásicos/química , Isoquinolinas/química , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Tiadiazoles/química , Tiazoles/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Dominio Catalítico , Cristalografía por Rayos X , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 2 Dependiente de la Ciclina/metabolismo , Isoquinolinas/síntesis química , Isoquinolinas/farmacocinética , Ratones , Neoplasias/tratamiento farmacológico , Fosforilación , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Relación Estructura-Actividad , Tiadiazoles/síntesis química , Tiadiazoles/farmacocinética , Tiazoles/síntesis química , Tiazoles/farmacocinéticaRESUMEN
Through a combination of screening and structure-based rational design, we have discovered a series of N(1)-(5-(heterocyclyl)-thiazol-2-yl)-3-(4-trifluoromethylphenyl)-1,2-propanediamines that were developed into potent ATP competitive inhibitors of AKT. Studies of linker strand-binding adenine isosteres identified SAR trends in potency and selectivity that were consistent with binding interactions observed in structures of the inhibitors bound to AKT1 and to the counter-screening target PKA. One compound was shown to have acceptable pharmacokinetic properties and to be a potent inhibitor of AKT signaling and of in vivo xenograft tumor growth in a preclinical model of glioblastoma.
Asunto(s)
Antineoplásicos/química , Azoles/química , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Azoles/farmacocinética , Azoles/uso terapéutico , Sitios de Unión , Cristalografía por Rayos X , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 2 Dependiente de la Ciclina/metabolismo , Diseño de Fármacos , Ratones , Ratones Desnudos , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
[reaction: see text] A series of 4-alkyl-5-aminoisoxazoles have been synthesized in high yield by nucleophilic addition of lithiated alkyl nitriles to (alpha)-chlorooximes. The scope and limitations of this reaction were examined by varying the nature of the nitrile and chloride oxime.