Inhibition of tumor cell growth, proliferation and migration by X-387, a novel active-site inhibitor of mTOR

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• 作者：Si-meng Chen^a ; Jia-li Liu^a ; Xiang Wang^a ; Chris Liang^b ; Jian Ding^a ; ^{jding@mail.shcnc.ac.cn} ; Ling-hua Meng^a ; ^{lhmeng@mail.shcnc.ac.cn}
• 关键词：X-387 ; mTOR kinase ; Cancer therapy ; Cell migration ; Autophagy
• 刊名：Biochemical Pharmacology
• 出版年：2012
• 期刊代码：2_00062952
• 类别：pha
• 出版时间：1 May, 2012
• 卷：83
• 期：9
• 页码：1183-1194
• 文件大小：1883 K

摘要

The mammalian target of rapamycin (mTOR), is deregulated in about 50%of human malignancies and exists in two complexes: mTORC1 and mTORC2. Rapalogs partially inhibit mTORC1 through allosteric binding to mTORC1 and their efficacy is modest as a cancer therapy. A few mTOR kinase inhibitors that inhibit both mTORC1 and mTORC2 have been reported to possess potent anticancer activities. Herein, we designed and synthesized a series of pyrazolopyrimidine derivatives targeting mTOR kinase domain and X-387 was identified as a promising lead. X-387 selectively inhibited mTOR in an ATP-competitive manner while sparing a panel of kinases from the PIKK family. X-387 blocked mTORC1 and mTORC2-mediacted signaling pathway in cell lines with activated mTOR signaling and in rapamycin-resistant cells. Specifically, X-387 inhibited phosphorylation of AKT at T308, which is thought to be a target of PDK1 but not mTOR. Such activity was not due to inhibition of PI3K since X-387 did not inhibit translocation of AKT to the cell membrane. X-387 induced autophagy as observed for other mTOR inhibitors, while induced autophagy is pro-survival since concurrent inhibition of autophagy by 3-MA reinforced the antiproliferative activity of mTOR inhibitors. X-387 also inhibited cell motility, which is associated with decrease in activity of small GTPases such as RhoA, Rac1 and Cdc42. Taken together, X-387 is a promising compound lead targeting mTOR and with a wide spectrum anticancer activity among tumor cell lines. The data also underscores the complexity of the mTOR signaling pathways which are far from being understood.