Current development of the second generation of mTOR inhibitors as anticancer agents

作     者：Hong-Yu Zhou Shi-Le Huang 

作者机构：Department of Biochemistry and Molecular Biology Feist-Weiller Cancer Center Louisiana State University Health Sciences Center 1501 Kings Highway Shreveport LA 71130-3932 USA. 

出 版 物：《Chinese Journal of Cancer》 (Chinese Journal of Cancer)

年 卷 期：2012年第31卷第1期

页      面：8-18页

核心收录：

学科分类：0710[理学-生物学] 071010[理学-生物化学与分子生物学] 1002[医学-临床医学] 0907[农学-林学] 07[理学] 08[工学] 0829[工学-林业工程] 09[农学] 

基　　金：supported in part by grants from NIH(CA115414 to S.H.) American Cancer Society(RSG-08-135-01-CNE to S.H.) 

主　　题：mTOR 抗癌药物 抑制剂 第二代 丝氨酸/苏氨酸蛋白激酶 蛋白质相互作用 雷帕霉素 细胞生长 

摘      要：The mammalian target of rapamycin (mTOR), a serine/threonine protein kinase, acts as a master switch for cellular anabolic and catabolic processes, regulating the rate of cell growth and proliferation. Dysregulation of the mTOR signaling pathway occurs frequently in a variety of human tumors, and thus, mTOR has emerged as an important target for the design of anticancer agents. mTOR is found in two distinct multiprotein complexes within cells, mTORC1 and mTORC2. These two complexes consist of unique mTOR-interacting proteins and are regulated by different mechanisms. Enormous advances have been made in the development of drugs known as mTOR inhibitors. Rapamycin, the first defined inhibitor of mTOR, showed effectiveness as an anticancer agent in various preclinical models. Rapamycin analogues (rapalogs) with better pharmacologic properties have been developed. However, the clinical success of rapalogs has been limited to a few types of cancer. The discovery that mTORC2 directly phosphorylates Akt, an important survival kinase, adds new insight into the role of mTORC2 in cancer. This novel finding prompted efforts to develop the second generation of mTOR inhibitors that are able to target both mTORC1 and mTORC2. Here, we review the recent advances in the mTOR field and focus specifically on the current development of the second generation of mTOR inhibitors as anticancer agents.