College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China.
Shandong Provincial Key Laboratory of Molecular Engineering, State Key Laboratory of Biobased Material and Green Papermaking, School of Chemistry and Chemical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China.
Molecules. 2022 Aug 19;27(16):5295. doi: 10.3390/molecules27165295.
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that belongs to the phosphoinositide 3-kinase (PI3K)-related kinase (PIKK) family. The kinase exists in the forms of two complexes, mTORC1 and mTORC2, and it participates in cell growth, proliferation, metabolism, and survival. The kinase activity is closely related to the occurrence and development of multiple human diseases. Inhibitors of mTOR block critical pathways to produce antiviral, anti-inflammatory, antiproliferative and other effects, and they have been applied to research in cancer, inflammation, central nervous system diseases and viral infections. Existing mTOR inhibitors are commonly divided into mTOR allosteric inhibitors, ATP-competitive inhibitors and dual binding site inhibitors, according to their sites of action. In addition, there exist several dual-target mTOR inhibitors that target PI3K, histone deacetylases (HDAC) or ataxia telangiectasia mutated and Rad-3 related (ATR) kinases. This review focuses on the structure of mTOR protein and related signaling pathways as well as the structure and characteristics of various mTOR inhibitors. Non-rapalog allosteric inhibitors will open new directions for the development of new therapeutics specifically targeting mTORC1. The applications of ATP-competitive inhibitors in central nervous system diseases, viral infections and inflammation have laid the foundation for expanding the indications of mTOR inhibitors. Both dual-binding site inhibitors and dual-target inhibitors are beneficial in overcoming mTOR inhibitor resistance.
哺乳动物雷帕霉素靶蛋白（mTOR）是一种丝氨酸/苏氨酸激酶，属于磷酸肌醇 3-激酶（PI3K）相关激酶（PIKK）家族。该激酶以两种复合物的形式存在，mTORC1 和 mTORC2，并参与细胞生长、增殖、代谢和存活。激酶活性与多种人类疾病的发生和发展密切相关。mTOR 的抑制剂可阻断关键途径，产生抗病毒、抗炎、抗增殖等作用，已应用于癌症、炎症、中枢神经系统疾病和病毒感染的研究。现有的 mTOR 抑制剂通常根据作用部位分为 mTOR 变构抑制剂、ATP 竞争性抑制剂和双结合位点抑制剂。此外，还有几种针对 PI3K、组蛋白去乙酰化酶（HDAC）或共济失调毛细血管扩张突变和 Rad-3 相关（ATR）激酶的双靶点 mTOR 抑制剂。本综述重点介绍 mTOR 蛋白及其相关信号通路的结构，以及各种 mTOR 抑制剂的结构和特性。非雷帕霉素变构抑制剂将为专门针对 mTORC1 的新型治疗药物的开发开辟新的方向。ATP 竞争性抑制剂在中枢神经系统疾病、病毒感染和炎症中的应用为扩大 mTOR 抑制剂的适应证奠定了基础。双结合位点抑制剂和双靶点抑制剂都有利于克服 mTOR 抑制剂耐药性。
