Title:The mTOR/4E-BP1/eIF4E Signalling Pathway as a Source of Cancer
Drug Targets
Volume: 29
Issue: 20
Author(s): Cristina Maracci, Stefano Motta, Alice Romagnoli, Matteo Costantino, Paola Perego*Daniele Di Marino
Affiliation:
- Molecular Pharmacology
Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
Keywords:
mTOR allosteric inhibitors, rapamycin, eIF4F, translational control, cancer, PIKKs.
Abstract: 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.
