Department of Cellular and Molecular Pharmacology, UC San Francisco, San Francisco, CA 94158, USA.
Curr Top Microbiol Immunol. 2010;347:241-62. doi: 10.1007/82_2010_64.
mTOR (mammalian Target of Rapamycin) is the hub of the phosphoinositide 3-Kinase (PI3-K)→Akt→mTOR pathway, which is one of the most commonly mutated pathways in cancer. PI3-Ks and mTOR are related kinases which share an evolutionarily related kinase domain, although the former is a lipid kinase and the latter is a protein kinase. As a result of their similar ATP sites, the prototypical PI3-K inhibitors LY294002 and wortmannin inhibit both kinases, although the compounds have been primarily thought of as inhibitors of PI3-Ks. The widespread use of these reagents to understand PI3-K signaling and the likelihood that many of their effects are confounded by dual inhibition of PI3-K and mTOR make it essential to develop selective mTOR inhibitors in part to understand the unique cellular effects of inhibition of this key downstream component in the growth factor pathway. Rapamycin has historically provided a means for selective mTOR inhibition, yet it is not a typical ATP competitive inhibitor, making its effects difficult to reconcile with LY294002 and wortmannin. Several groups have recently reported pharmacological agents which inhibit mTOR but not PI3-K, providing a new pharmacological approach to selective mTOR inhibition. The TOR kinase domain inhibitors of mTOR have been termed TORKinibs to distinguish their mode of action from rapamycin and its analogs (rapalogs). These inhibitors bind to the ATP binding site of the kinase domain of mTOR and as a result inhibit both mTOR complexes, TORC1 (rapamycin sensitive) and TORC2 (rapamycin resistant). These molecules have allowed a reinvestigation of mTOR and in particular a reinvestigation of the mechanistic basis for incomplete proliferative arrest of cells by Rapamycin. A consensus has quickly emerged from the study of various TORKinibs that Rapamycin is ineffective at blocking cell proliferation because it only partially inhibits the activity of mTORC1. The profound anti-proliferative effect of TORKinibs suggests that as the molecules enter the clinic they may be successful in the treatment of cancers where rapamycin has failed.
mTOR（哺乳动物雷帕霉素靶蛋白）是磷酸肌醇 3-激酶（PI3-K）→Akt→mTOR 途径的枢纽，该途径是癌症中最常发生突变的途径之一。PI3-Ks 和 mTOR 是相关激酶，它们共享一个进化上相关的激酶结构域，尽管前者是一种脂质激酶，而后者是一种蛋白激酶。由于它们的相似的 ATP 结合位点，原型 PI3-K 抑制剂 LY294002 和渥曼青霉素抑制这两种激酶，尽管这些化合物主要被认为是 PI3-Ks 的抑制剂。由于它们广泛用于了解 PI3-K 信号转导，并且它们的许多作用可能由于对 PI3-K 和 mTOR 的双重抑制而变得复杂，因此开发选择性 mTOR 抑制剂至关重要，部分原因是为了了解生长因子途径中关键下游成分抑制的独特细胞效应。雷帕霉素历来提供了一种选择性 mTOR 抑制的方法，但它不是一种典型的 ATP 竞争性抑制剂，这使得其作用难以与 LY294002 和渥曼青霉素协调一致。最近有几个小组报告了抑制 mTOR 但不抑制 PI3-K 的药理学试剂，为选择性 mTOR 抑制提供了一种新的药理学方法。mTOR 的 TOR 激酶结构域抑制剂被称为 TORKinibs，以将其作用模式与雷帕霉素及其类似物（rapalogs）区分开来。这些抑制剂结合到 mTOR 激酶结构域的 ATP 结合位点，因此抑制了两种 mTOR 复合物，TORC1（雷帕霉素敏感）和 TORC2（雷帕霉素抗性）。这些分子使人们能够重新研究 mTOR，特别是重新研究雷帕霉素不完全抑制细胞增殖的机制基础。各种 TORKinibs 的研究迅速达成共识，即雷帕霉素在阻止细胞增殖方面无效，因为它仅部分抑制 mTORC1 的活性。TORKinibs 的显著抗增殖作用表明，随着这些分子进入临床，它们可能在雷帕霉素治疗失败的癌症治疗中取得成功。
