Rapamycin and mTOR kinase inhibitors.
Rapamycin and mTOR kinase inhibitors.
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DOI：
10.1007/s12154-008-0003-5
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发表时间：
2008-11-01
期刊：
影响因子：
--
通讯作者：
Lin, Richard Z
中科院分区：
文献类型：
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作者：
Ballou, Lisa M;Lin, Richard Z
哺乳动物雷帕霉素靶蛋白（mTOR）是一种控制细胞生长、增殖和存活的蛋白激酶。mTOR信号转导在癌症中经常上调，并且人们对开发靶向这种酶的药物非常感兴趣。雷帕霉素及其类似物结合到与催化位点分开的结构域以阻断mTOR功能的子集。这些药物对mTOR具有极高的选择性，并且已经在临床上用于治疗癌症，但它们可能会激活mTOR依赖性生存途径，从而导致治疗失败。相比之下，在催化位点与ATP竞争的小分子会抑制mTOR的所有激酶依赖性功能，而不会激活存活途径。已经描述了几种非选择性mTOR激酶抑制剂，在这里，我们回顾了它们的化学和细胞特性。选择性mTOR激酶抑制剂的进一步开发有望产生具有新作用机制的有效抗癌药物。
Mammalian target of rapamycin (mTOR) is a protein kinase that controls cell growth, proliferation, and survival. mTOR signaling is often upregulated in cancer and there is great interest in developing drugs that target this enzyme. Rapamycin and its analogs bind to a domain separate from the catalytic site to block a subset of mTOR functions. These drugs are extremely selective for mTOR and are already in clinical use for treating cancers, but they could potentially activate an mTOR-dependent survival pathway that could lead to treatment failure. By contrast, small molecules that compete with ATP in the catalytic site would inhibit all of the kinase-dependent functions of mTOR without activating the survival pathway. Several non-selective mTOR kinase inhibitors have been described and here we review their chemical and cellular properties. Further development of selective mTOR kinase inhibitors holds the promise of yielding potent anticancer drugs with a novel mechanism of action.