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
Activation of the PI3K/Akt/mTOR kinase pathway is frequently associated with human cancer. Selective inhibition of p70S6Kinase, which is the last kinase in the PI3K pathway, is not sufficient for strong tumor growth inhibition and can lead to activation of upstream proteins including Akt through relief of a negative feedback loop. Targeting multiple sites in the PI3K pathway might be beneficial for optimal activity. In this manuscript we report the design of dual Akt/p70S6K inhibitors and the evaluation of the lead compound 11b in vivo, which was eventually advanced into clinical development.
Asunto(s)
Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Pirazoles/síntesis química , Pirazoles/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Proteínas Quinasas S6 Ribosómicas 70-kDa/antagonistas & inhibidores , Animales , Perros , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Haplorrinos , Humanos , Ratones , Microsomas/efectos de los fármacos , Modelos Moleculares , Estructura Molecular , Fosfatidilinositol 3-Quinasas/efectos de los fármacos , Pirazoles/química , Piridinas/químicaRESUMEN
The 70-kDa ribosomal protein S6 kinase (p70S6K) is part of the PI3K/AKT/mTOR pathway and has been implicated in cancer. High throughput screening versus p70S6K led to the identification of aminopyrimidine 3a as active inhibitor. Lead optimization of 3a resulted in highly potent, selective, and orally bioavailable pyrazolopyrimidines. In this manuscript we report the structure-activity relationship of this series and pharmacokinetic, pharmacodynamic, and efficacy data of the lead compound 13c.
