Erschienen in:
01.02.2013 | PRECLINICAL STUDIES
Biological characterization of ETP-46321 a selective and efficacious inhibitor of phosphoinositide-3-kinases
verfasst von:
Teresa G. Granda, David Cebrián, Sonia Martínez, Patricia Villanueva Anguita, Estela Casas López, Wolfgang Link, Teresa Merino, Joaquín Pastor, Beatriz G. Serelde, Sandra Peregrina, Irene Palacios, Maria Isabel Albarran, Antonio Cebriá, Milagros Lorenzo, Patricia Alonso, Jesús Fominaya, Ana Rodríguez López, James R. Bischoff
Erschienen in:
Investigational New Drugs
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Ausgabe 1/2013
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Summary
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 \( {\text{K}}_{\text{i}}^{\text{app}} = {2}.{\text{4 nM}} \). The compound was 6 times less potent towards PI3Kδ and more than 200 and 60 times less potent at inhibiting PI3Kβ and PI3Kγ and did not significantly inhibit the related phosphoinositide-3-kinase-related protein kinase family kinases mTOR or DNA PK (IC50’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.