第二代 mTOR 抑制剂的抗肿瘤研究进展

哺乳动物雷帕霉素靶蛋白(mTOR)是 PI3K/Akt/mTOR 等多种信号通路的下游分子,在细胞增殖、分化、转移和存活中发挥 重要作用,已成为癌症治疗的一个重要靶标。传统的 mTOR 抑制剂主要是雷帕霉素及其衍生物,能特异性抑制 mTORC1,但在部分癌 症临床治疗中未达到预期疗效,且易产生耐药性。第二代 mTOR 抑制剂即双重或多重 mTOR 抑制剂能与 mTOR 的催化位点竞争 ATP, 高度选择性地抑制 mTORC1 和 mTORC2,比单靶点 mTOR 抑制剂具有更大的治疗优势。此外,某些天然来源产物也具有对 mTOR 的 抑制作用,且毒性、副作用更小。综述近几年有关 mTOR 及其抑制剂在抗肿瘤方面的研究进展。

Research Progress in Anti-tumor Activity of the Second Generation mTOR Inhibitors

As a downstream molecule of various pathways such as PI3K/Akt/mTOR pathway, mTOR plays important roles in cell proliferation, differentiation, metastasis and survival, emerging as a key protein target of anticancer drugs. Traditional mTOR inhibitors, rapamycin and its analogs, can effectively inhibit mTORC1, but suffer from limited clinical ef cacy and easy development of drug resistance. The second generation mTOR inhibitors are dual or multiple mTOR inhibitors that can compete with the catalytic site of mTOR for ATP and inhibit both mTORC1 and mTORC2 with a high selectivity, showing advantages over single inhibitors. Furthermore, some natural compounds have been found to inhibit mTOR with low toxicity and less side effects. In this paper, we reviewed the latest research in mTOR and its inhibitors as anticancer drugs.