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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 4E-BPs, 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.

Nonsense-mediated mRNA decay (NMD) is a pathway that detects and degrades mRNAs containing premature translation termination codons (PTCs). In humans, recognition of these aberrant mRNAs requires an exon-junction-complex (EJC) placed downstream of a PTC and the dynamic interaction of several UPF/SMG proteins, the ribosome and the EJC. These interactions promote UPF1 phosphorylation by SMG1 kinase, triggering mRNA degradation. Recent progress in our understanding of NMD has been achieved by combining cryo-electron microscopy, high-resolution structures, interaction data and functional assays. These studies uncovered a mechanism regulating SMG1 kinase as well as the architecture and functional implications of a complex containing UPF1, UPF2, UPF3 and EJC. Collectively these findings reveal the role of protein scaffolds and conformational changes in NMD regulation.