摘要
雷帕霉素的机制/哺乳动物靶点(mTOR)是调节细胞生命周期中关键步骤的信号通路的关键枢纽。一旦加入mTORC1复合物,mTOR就会磷酸化真核起始因子4E(eIF4E)结合蛋白1(4E-BP1),然后释放eIF4E。当不与4个ebp结合时,eIF4E识别mRNA5‘-cap结构,并与eIF4A和eIF4G一起形成eIF4F复合物,招募mRNA上的核糖体。在正常情况下,eIF4E的细胞浓度很低,这使得eIF4E成为蛋白质合成起始的限制因子。绝大多数癌症类型的特征是同时mTOR/4E-BP1信号通路解除和eIF4E上调,导致促癌促进基因的表达增加和细胞生长解除。在过去的几十年里,越来越多的mTOR/4E-BP1/eIF4E通路的选择性抑制剂被发现或设计出来。几种令人鼓舞的临床前结果的抑制剂已经在临床试验中进行了测试。本文综述了针对mTOR、4E-BP1和eIF4E的药物开发的最新研究,描述了最有前途的化合物的设计原理和可用的结构和功能数据。
关键词: mTOR变构抑制剂,雷帕霉素,eIF4F,转译控制,癌症,PIKKs。
Current Medicinal Chemistry
Title:The mTOR/4E-BP1/eIF4E Signalling Pathway as a Source of Cancer Drug Targets
Volume: 29 Issue: 20
关键词: mTOR变构抑制剂,雷帕霉素,eIF4F,转译控制,癌症,PIKKs。
摘要: The mechanistic/mammalian target of rapamycin (mTOR) is the crucial hub of signalling pathways that regulate essential steps in the cell life cycle. Once incorporated in the mTORC1 complex, mTOR phosphorylates the eukaryotic initiation factor 4E (eIF4E)- binding protein 1 (4E-BP1), which then releases eIF4E. When not bound to 4EBPs, eIF4E recognizes the mRNA 5’-cap structure and, together with eIF4A and eIF4G, it forms the eIF4F complex that recruits the ribosome on the mRNA. Under normal conditions, the cellular concentration of eIF4E is very low, making eIF4E the limiting factor in the initiation of protein synthesis. The vast majority of cancer types are characterized by the simultaneous deregulation of the mTOR/4E-BP1 signalling pathway and upregulation of eIF4E, which lead to an increased expression of cancer-promoting genes and deregulated cellular growth. Over the last decades, a growing number of selective inhibitors of the mTOR/4E-BP1/eIF4E pathway have been discovered or designed. Several inhibitors with encouraging preclinical results have been tested in clinical trials. This review summarizes the most recent research on drug development against mTOR, 4E-BP1, and eIF4E, describing the design rationale and the available structural and functional data on the most promising compounds.
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The mTOR/4E-BP1/eIF4E Signalling Pathway as a Source of Cancer Drug Targets, Current Medicinal Chemistry 2022; 29 (20) . https://dx.doi.org/10.2174/0929867329666220224112042
DOI https://dx.doi.org/10.2174/0929867329666220224112042 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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