Liu Qingsong, Thoreen Carson, Wang Jinhua, Sabatini David, Gray Nathanael S
Department of Cancer Biology, Dana Farber Cancer Institute, 44 Binney Street, Boston, MA 02115.
Drug Discov Today Ther Strateg. 2009 Summer;6(2):47-55. doi: 10.1016/j.ddstr.2009.12.001.
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.
雷帕霉素的哺乳动物靶点（mTOR）是一种在进化上保守的丝氨酸/苏氨酸激酶，是调节细胞生长和分裂许多基本特征的信号通路的创始成员。在细胞中，mTOR作为两种功能不同的复合物的催化亚基，分别称为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。与其作为促进生长途径的作用一致，大量研究发现Mtor信号在广泛的人类癌症中过度激活。特别是，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，部分原因是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通过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综述。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。
