PI3K/AKT/mTOR通路
PTEN公司
抑制器
蛋白激酶B
激酶
癌症研究
细胞生长
化学
mTOR抑制剂的发现与发展
体内
药物发现
计算生物学
生物
癌症
信号转导
药理学
生物化学
遗传学
作者
Hengmiao Cheng,Shubha Bagrodia,Simon Bailey,Martin P. Edwards,Justin Hoffman,Qiyue Hu,Robert S. Kania,Daniel R. Knighton,Matthew A. Marx,Sacha Ninkovic,Shaoxian Sun,Eric Zhang
出处
期刊:MedChemComm
[The Royal Society of Chemistry]
日期:2010-01-01
卷期号:1 (2): 139-139
被引量:68
摘要
The phosphatidylinositol 3-kinase (PI3K) signaling pathway plays crucial roles in cell growth, proliferation and survival. Genomic aberrations in the PI3K pathway, such as mutational activation of PI3Kα or loss of function of tumor suppressor PTEN, have been closely linked to the development and progression of a wide range of cancers. Hence, inhibition of the key targets in the pathway, e.g. PI3K, AKT, mTOR, offers great potential for the treatment of cancer. Lead optimization through integration of structure based drug design (SBDD) and physical properties-based optimization (PPBO) led to the discovery of 2-amino-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PF-04691502, 1) that demonstrated potent in vitro inhibitory activity against both PI3K and mTOR, excellent kinase selectivity, good ADMET, and robust in vivo efficacy in a mouse xenograft tumor growth model. Compound 1 is currently being evaluated in human clinical trials for the treatment of cancer.
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