PI3K/AKT/mTOR通路
mTORC2型
mTORC1型
蛋白激酶B
RPTOR公司
激酶
生物
癌症研究
细胞生长
癌细胞
雷帕霉素的作用靶点
细胞生物学
化学
磷酸化
生物化学
信号转导
癌症
遗传学
作者
Ker Yu,Lourdes Toral‐Barza,Celine Shi,Weiguo Zhang,Judy Lucas,Boris Shor,Jamie Kim,Jeroen C. Verheijen,Kevin J. Curran,David J. Malwitz,Derek C. Cole,John W. Ellingboe,Semiramis Ayral‐Kaloustian,Tarek S. Mansour,James J. Gibbons,Robert T. Abraham,Paweł Nowak,Arie Zask
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2009-07-29
卷期号:69 (15): 6232-6240
被引量:312
标识
DOI:10.1158/0008-5472.can-09-0299
摘要
Abstract The mammalian target of rapamycin (mTOR) is centrally involved in cell growth, metabolism, and angiogenesis. While showing clinical efficacy in a subset of tumors, rapamycin and rapalogs are specific and allosteric inhibitors of mTOR complex 1 (mTORC1), but they do not directly inhibit mTOR complex 2 (mTORC2), an emerging player in cancer. Here, we report chemical structure and biological characterization of three pyrazolopyrimidine ATP-competitive mTOR inhibitors, WAY-600, WYE-687, and WYE-354 (IC50, 5–9 nmol/L), with significant selectivity over phosphatidylinositol 3-kinase (PI3K) isofoms (>100-fold). Unlike the rapalogs, these inhibitors acutely blocked substrate phosphorylation by mTORC1 and mTORC2 in vitro and in cells in response to growth factor, amino acids, and hyperactive PI3K/AKT. Unlike the inhibitors of PI3K or dual-pan PI3K/mTOR, cellular inhibition of P-S6K1(T389) and P-AKT(S473) by the pyrazolopyrimidines occurred at significantly lower inhibitor concentrations than those of P-AKT(T308) (PI3K-PDK1 readout), showing mTOR selectivity in cellular setting. mTOR kinase inhibitors reduced AKT downstream function and inhibited proliferation of diverse cancer cell lines. These effects correlated with a strong G1 cell cycle arrest in both the rapamycin-sensitive and rapamycin-resistant cells, selective induction of apoptosis, repression of global protein synthesis, and down-regulation of angiogenic factors. When injected into tumor-bearing mice, WYE-354 inhibited mTORC1 and mTORC2 and displayed robust antitumor activity in PTEN-null tumors. Together, our results highlight mechanistic differentiation between rapalogs and mTOR kinase inhibitors in targeting cancer cell growth and survival and provide support for clinical development of mTOR kinase inhibitors as new cancer therapy. [Cancer Res 2009;69(15):OF6232–9]
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