mTOR抑制剂的研究概况

A Review of Research on mTOR Inhibitors

mTOR是哺乳动物雷帕霉素靶蛋白,是一种丝氨酸/苏氨酸激酶.在细胞中,mTOR以mTORC1和mTORC2的催化亚基形式存在,这两种复合物参与细胞基因转录、蛋白质翻译起始、核糖体生物合成、细胞凋亡等过程.mTOR信号通路调控异常与肿瘤发生密切相关.抑制mTOR通路可以有效阻断各种生长因子异常信号的转导,从而抑制癌症的发生、发展.传统的mTOR抑制剂主要是雷帕霉素及其衍生物,其中坦西莫司和依维莫司已被批准用于治疗肾细胞癌,雷帕霉素和ridaforolimus正在进行临床评价.此外,人们发现了许多mTOR小分子抑制剂,包括一些PI3K/mTOR双重抑制剂,其中NVP-BEZ235,PKI587,PKI179,GSK2126458,AZD8055,WYE-354等小分子抑制剂已进入临床阶段.

mTOR, a serine/threonine kinase, is a target molecule of rapamycin. In ceils, mTOR acts as the catalytic subunit of two functionally distinct complexes, called mTORC1 and mTORC2. These complexes coordinate a variety of processes that include gene transcription, protein translation initiation, ribosome bio- synthesis, apoptosis and many other biological processes. Dysregulation of mTOR signal pathway is closely related with tumorigenesis. Inhibition of mTOR pathway leads to an effective block of abnormal signal transduction and blocks the development of cancer. Traditional mTOR inhibitors are rapamycin and its derivatives, among which everolimus and temsirolimus have already been approved for the treatment of renal-cell carcinoma. In addition, a number of small molecule inhibitors of roTOR, including several PI3K/mTOR dual inhibitors, have been developed. NVP-BEZ235, PKI587, PKI179, GSK2126458, AZDS055 and WYE-354 have entered the clinical stage.