期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 20, 期 8, 页码 2586-2590出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2010.02.082
关键词
Kinase; Phosphatidylinositol-3-kinases; Mammalian target of rapamycin
A series of benzofuran-3-one indole phosphatidylinositol-3-kinases (PI3K) inhibitors identified via HTS has been prepared. The optimized inhibitors possess single digit nanomolar activity against p110 alpha (PI3K-alpha), good pharmaceutical properties, selectivity versus p110 gamma (PI3K-gamma), and tunable selectivity versus the mammalian target of rapamycin ( mTOR). Modeling of compounds 9 and 32 in homology models of PI3K-alpha and mTOR supports the proposed rationale for selectivity. Compounds show activity in multiple cellular proliferation assays with signaling through the PI3K pathway confirmed via phospho-Akt inhibition in PC-3 cells. (C) 2010 Elsevier Ltd. All rights reserved.
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