期刊
INVESTIGATIONAL NEW DRUGS
卷 31, 期 1, 页码 66-76出版社
SPRINGER
DOI: 10.1007/s10637-012-9835-5
关键词
PI3K inhibitor; ETP-46321; Cancer therapeutics
资金
- Spanish Ministry of Science and Innovation (MICINN) [CIT-090100-2007-48]
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 PI3K alpha . The compound was 6 times less potent towards PI3K delta and more than 200 and 60 times less potent at inhibiting PI3K beta and PI3K gamma and did not significantly inhibit the related phosphoinositide-3-kinase-related protein kinase family kinases mTOR or DNA PK (IC50's > 5 mu M), 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.
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