哺乳动物西罗莫司靶蛋白的生物功能及其抑制剂研究进展

Biological function and inhibitors of mTOR:research advances

哺乳动物西罗莫司靶蛋白(mammalian target of sirolimus,mTOR)参与细胞周期调控的多个步骤,是调节细胞生长的关键蛋白,在细胞中以两种复合物的形式存在,即mTORC1和mTORC2。mTOR被异常激活后会促使癌细胞的高速分化,而其活性被抑制后能使细胞周期阻滞在G1期。近几年的研究证明,mTOR是抗癌、免疫抑制和抗衰老治疗的重要靶点。根据作用位点不同,以mTOR为靶点的抑制剂主要分为两类,即作用于FKBP12蛋白连接区的西罗莫司衍生物和作用于ATP连接区的小分子化合物。现已有多种用于抗癌或免疫抑制的西罗莫司衍生物类药物上市,而针对ATP竞争性mTOR抑制剂的研究也成为热点。

Mammalian target of sirolimus（mTOR） has been involved in multi-step of cell cycle-regulation and is the key protein regulating cell growth. In cells, mTOR acts as two functionally distinct complexes, called mTORC1 and mTORC2.Overactivating of mTOR will lead to the rapid differentiation of cancer cell, on the contrary, inhibiting of mTOR will cause cells to arrest growth in G1 phase. The researches in recent years demonstrate that mTOR is a significant target for anticancer, immunodepression and anti-aging. According to the different binging points, the mTOR inhibitors can be subclassified into two types： sirolimus derivatives and ATP analogues which act on FKBP12-sirolimus-binding region and ATP-binding region respectively. A series of sirolimus derivatives have been approved by FDA for marketing, and the research on ATP analogues have also become a hot area.