RESUMEN
In PTEN-mutated tumors, we show that PI3Kα activity is suppressed and PI3K signaling is driven by PI3Kß. A selective inhibitor of PI3Kß inhibits the Akt/mTOR pathway in these tumors but not in those driven by receptor tyrosine kinases. However, inhibition of PI3Kß only transiently inhibits Akt/mTOR signaling because it relieves feedback inhibition of IGF1R and other receptors and thus causes activation of PI3Kα and a rebound in downstream signaling. This rebound is suppressed and tumor growth inhibition enhanced with combined inhibition of PI3Kα and PI3Kß. In PTEN-deficient models of prostate cancer, this effective inhibition of PI3K causes marked activation of androgen receptor activity. Combined inhibition of both PI3K isoforms and androgen receptor results in major tumor regressions.
Asunto(s)
Compuestos de Anilina/farmacología , Cromonas/farmacología , Neoplasias/tratamiento farmacológico , Fosfohidrolasa PTEN/genética , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Tiazoles/farmacología , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Trasplante de Neoplasias , Neoplasias/genética , Neoplasias/patología , Transducción de Señal/efectos de los fármacosRESUMEN
We have identified a new series of C-5 substituted indazolylaminoquinazolines as potent erbB2 kinase inhibitors. The lead compound 22 showed excellent in vitro potency, good physical properties, acceptable oral pharmacokinetics in rat and dog, and low human in vitro clearance. It showed at least equivalent activity dose for dose compared to lapatinib in various erbB2- or EGFR-driven xenograft models after chronic oral administration.
Asunto(s)
Antineoplásicos/farmacología , Receptores ErbB/antagonistas & inhibidores , Indazoles/farmacología , Neoplasias Experimentales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/farmacología , Receptor ErbB-2/antagonistas & inhibidores , Administración Oral , Animales , Antineoplásicos/síntesis química , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Perros , Factor de Crecimiento Epidérmico/farmacología , Canales de Potasio Éter-A-Go-Go , Femenino , Hepatocitos/citología , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Indazoles/síntesis química , Queratinocitos/citología , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Lapatinib , Masculino , Tasa de Depuración Metabólica , Ratones , Ratones Desnudos , Ratones SCID , Microsomas/efectos de los fármacos , Estructura Molecular , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Quinazolinas/síntesis química , Ratas , Ratas Wistar , Tasa de Supervivencia , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Starting from initial lead 1 containing a basic 5-substituent, optimisation of the glycolamide-derived neutral 5-substituent led to potent inhibitors of erbB2 with good pharmacokinetics. Representative compounds 19 and 21 inhibited phosphorylation of erbB2 in a mouse BT474C xenograft model after oral administration.