Biological characterization of ETP-46321 a selective and efficacious inhibitor of phosphoinositide-3-kinases

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 . The compound was...

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Published in:Investigational new drugs 2013-02, Vol.31 (1), p.66-76
Main Authors: Granda, Teresa G., Cebrián, David, Martínez, Sonia, Anguita, Patricia Villanueva, López, Estela Casas, Link, Wolfgang, Merino, Teresa, Pastor, Joaquín, Serelde, Beatriz G., Peregrina, Sandra, Palacios, Irene, Albarran, Maria Isabel, Cebriá, Antonio, Lorenzo, Milagros, Alonso, Patricia, Fominaya, Jesús, López, Ana Rodríguez, Bischoff, James R.
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - blood
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Biological and medical sciences
Cell Line, Tumor
Cell Proliferation - drug effects
Enzyme Inhibitors - blood
Enzyme Inhibitors - pharmacology
Enzyme Inhibitors - therapeutic use
Female
General pharmacology
Humans
Imidazoles - blood
Imidazoles - pharmacology
Imidazoles - therapeutic use
Medical sciences
Medicine
Medicine & Public Health
Mice
Mice, Inbred BALB C
Mice, SCID
Oncology
Pharmaceutical technology. Pharmaceutical industry
Pharmacology. Drug treatments
Pharmacology/Toxicology
Phosphatidylinositol 3-Kinases - antagonists & inhibitors
Phosphatidylinositol 3-Kinases - metabolism
Preclinical Studies
Pyrazines - blood
Pyrazines - pharmacology
Pyrazines - therapeutic use
Xenograft Model Antitumor Assays
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Summary: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 . 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 (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.
ISSN:0167-6997
1573-0646
DOI:10.1007/s10637-012-9835-5