Li Huawei, Cotton Jennifer L, Guertin David A
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
Methods Mol Biol. 2012;821:329-47. doi: 10.1007/978-1-61779-430-8_21.
Extensive efforts are underway to develop small-molecule inhibitors of the mammalian target of rapamycin (mTOR) kinase. It is hoped that these inhibitors will have widespread clinical impact in oncology because mTOR is a major downstream effector of PI3K signaling, one of the most frequently activated pathways in cancer. In cells, mTOR is the catalytic core subunit of two distinct complexes, mTORC1 and mTORC2, which are defined by unique mTOR-interacting proteins and have unique functions downstream of PI3K. Two classes of mTOR inhibitors are currently being evaluated as cancer therapeutics: rapamycin and its analogs, which partially inhibit mTORC1 and in some cell types mTORC2, and the recently described ATP-competitive inhibitors, which inhibit the kinase activity of both complexes. Although small molecules that selectively target mTORC2 do not yet exist, experiments using mouse genetics suggest that a theoretical mTORC2 inhibitor may have significant therapeutic value. Here, we discuss an approach to model mTOR complex specific inhibitors using mouse genetics and how it can be applied to other gene products involved in oncogenic signaling to which inhibitors do not exist.
目前正在进行广泛的努力来开发雷帕霉素哺乳动物靶点（mTOR）激酶的小分子抑制剂。人们希望这些抑制剂将在肿瘤学领域产生广泛的临床影响，因为mTOR是PI3K信号传导的主要下游效应器，而PI3K信号传导是癌症中最常被激活的途径之一。在细胞中，mTOR是两种不同复合物mTORC1和mTORC2的催化核心亚基，这两种复合物由独特的mTOR相互作用蛋白定义，并在PI3K下游具有独特的功能。目前有两类mTOR抑制剂正在作为癌症治疗药物进行评估：雷帕霉素及其类似物，它们部分抑制mTORC1，在某些细胞类型中还抑制mTORC2；以及最近描述的ATP竞争性抑制剂，它们抑制这两种复合物的激酶活性。尽管目前还不存在选择性靶向mTORC2的小分子，但利用小鼠遗传学进行的实验表明，一种理论上的mTORC2抑制剂可能具有显著的治疗价值。在这里，我们讨论一种利用小鼠遗传学对mTOR复合物特异性抑制剂进行建模的方法，以及如何将其应用于其他参与致癌信号传导但不存在抑制剂的基因产物。
