mTOR Mediated Anti-Cancer Drug Discovery.
mTOR Mediated Anti-Cancer Drug Discovery.
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DOI：
10.1016/j.ddstr.2009.12.001
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发表时间：
2009
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哺乳动物雷帕霉素靶蛋白 (mTOR) 是一种进化上保守的丝氨酸/苏氨酸激酶，也是调节细胞生长和分裂的许多基本特征的信号通路的创始成员。在细胞中，mTOR 充当两个功能不同的复合物的催化亚基，称为 mTOR 复合物 1 (mTORC1) 和 mTOR 复合物 2 (mTORC2)。这些复合物共同协调各种过程，包括蛋白质翻译、自噬、增殖、存活和代谢，以响应营养、能量和生长因子信号。与其作为生长促进途径的作用一致，大量研究发现 Mtor 信号在多种人类癌症中高度激活。尤其是，mTORC2 被认为是磷脂酰肌醇 3 激酶 (PI3K) 信号通路的主要效应器，该信号通路在大多数人类癌症中发生突变，部分原因在于其磷酸化和调节原癌基因 Akt/PKB 的能力。 mTOR 的许多生物学功能已使用天然产物雷帕霉素进行了药理学探索，雷帕霉素是一种变构抑制剂，已在其他地方进行了广泛的审查。本综述将特别关注 mTOR 小分子 ATP 竞争性抑制剂的开发及其作为靶向治疗的前景。
The mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase and the founding member of a signaling pathway that regulates many fundamental features of cell growth and division. In cells, mTOR acts as the catalytic subunit of two functionally distinct complexes, called mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2). Together, these complexes coordinate a variety of processes that include protein translation, autophagy, proliferation, survival and metabolism in response to nutrient, energy and growth factor signals. Consistent with its role as a growth-promoting pathway, numerous studies have found that Mtor signaling is hyper-activated in a broad spectrum of human cancers. In particular, mTORC2 is considered a primary effector of the phosphatidylinositol-3-kinase (PI3K) signaling pathway, which is mutated in a majority of human cancers, in part through its ability to phosphorylate and regulate the proto-oncogene Akt/PKB. Many biological functions of mTOR have been pharmacologically explored using the natural product rapamycin, an allosteric inhibitor that has been reviewed extensively elsewhere. This review will focus specifically on the development of small molecule ATP-competitive inhibitors of mTOR and their prospects as a targeted therapy.