RESUMEN
Inhibitors of PI3K signaling are of great therapeutic interest in oncology. The phosphoinositide-3-kinase signaling pathway is activated in a variety of solid and non-solid tumors. We have identified an imidazopyrazine derivative, ETP-46321, as a potent inhibitor of PI3Kα [Formula: see text]. The compound was 6 times less potent towards PI3Kδ and more than 200 and 60 times less potent at inhibiting PI3Kß and PI3Kγ and did not significantly inhibit the related phosphoinositide-3-kinase-related protein kinase family kinases mTOR or DNA PK (IC(50)'s > 5 µM), or an additional 287 protein kinases that were screened. ETP-46321 inhibited PI3K signaling in treated tumor cell lines, induced cell cycle arrest and inhibited VEGF-dependent sprouting of HUVEC cells. The compound was anti-proliferative and synergized with both cytotoxic and targeted therapeutics. The compound induced a reduction in the phosphorylation of Akt in U87 MG xenografts after a single treatment. The growth of colon and lung cancinoma HT-29 and A549 xenografts was delayed by once a day treatment with ETP-46321. The compound synergized with Doxotaxel in a model of ovarian cancer.
Asunto(s)
Antineoplásicos/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Imidazoles/uso terapéutico , Inhibidores de las Quinasa Fosfoinosítidos-3 , Pirazinas/uso terapéutico , Animales , Antineoplásicos/sangre , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Inhibidores Enzimáticos/sangre , Inhibidores Enzimáticos/farmacología , Femenino , Humanos , Imidazoles/sangre , Imidazoles/farmacología , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Fosfatidilinositol 3-Quinasas/metabolismo , Pirazinas/sangre , Pirazinas/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The serine/threonine Pim 1 kinase is an oncogene whose expression is deregulated in several human cancers. Overexpression of Pim 1 facilitates cell cycle progression and suppresses apoptosis. Hence pharmacologic inhibitors of Pim 1 are of therapeutic interest for cancer. ETP-45299 is a potent and selective inhibitor of Pim 1 that inhibits the phosphorylation of Bad and 4EBP1 in cells and suppresses the proliferation of several non-solid and solid human tumor cell lines. The combination of the PI3K inhibitor GDC-0941 with ETP-45299 was strongly synergistic in MV-4-11 AML cells, indicating that the combination of selective Pim kinase inhibitors and PI3K inhibitor could have clinical benefit.