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首页> 外文期刊>Biochemical Pharmacology >Inhibition of tumor cell growth, proliferation and migration by X-387, a novel active-site inhibitor of mTOR
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Inhibition of tumor cell growth, proliferation and migration by X-387, a novel active-site inhibitor of mTOR

机译：X-387（一种新型的mTOR活性位点抑制剂）抑制肿瘤细胞的生长，增殖和迁移

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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.
机译：雷帕霉素（mTOR）的哺乳动物靶标在约50％的人类恶性肿瘤中被释放，并以两种复合物形式存在：mTORC1和mTORC2。雷帕糖通过与mTORC1的变构结合部分抑制mTORC1，其作为癌症疗法的疗效不高。据报道，同时抑制mTORC1和mTORC2的几种mTOR激酶抑制剂具有有效的抗癌活性。本文中，我们设计并合成了一系列靶向mTOR激酶结构域的吡唑并嘧啶衍生物，X-387被确定为有前途的先导。 X-387以ATP竞争方式选择性抑制mTOR，同时保留了PIKK家族的一组激酶。 X-387在激活了mTOR信号的细胞系中和雷帕霉素抗性细胞中阻断了mTORC1和mTORC2介导的信号通路。具体而言，X-387在T308抑制了AKT的磷酸化，T308被认为是PDK1的靶标，但不是mTOR的靶标。由于X-387不会抑制AKT向细胞膜的转运，因此这种活性不是由于PI3K的抑制。如其他mTOR抑制剂所观察到的，X-387诱导自噬，而诱导自噬是存活的，因为3-MA同时抑制自噬增强了mTOR抑制剂的抗增殖活性。 X-387还抑制细胞运动，这与小GTP酶（如RhoA，Rac1和Cdc42）的活性降低有关。综上所述，X-387是靶向mTOR的有前途的化合物铅，在肿瘤细胞系中具有广谱抗癌活性。数据还强调了mTOR信号通路的复杂性，这是人们尚未了解的。

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