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Chemical Probes for Studying the Eukaryotic Translation Initiation Factor 4E (eIF4E)-Regulated Translatome in Cancer
Rachel L O'Rourke1, Amanda L Garner1
1Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.
Abstract:
The dysregulation of translation is a hallmark of cancer that enables rapid changes in the cell proteome to shape oncogenic phenotypes that promote tumor survival. The predominant signaling pathways leading to dysregulation of translational control in cancer are the PI3K-AKT-mTORC1, RAS-RAF-MAPK, and MYC pathways, which all converge on eukaryotic translation initiation factor 4E (eIF4E), an RNA-binding protein that binds to the m7GpppX cap structure at the 5' end of mRNAs to initiate cap-dependent translation. eIF4E is the rate-limiting factor of translation initiation, and its overexpression is known to drive oncogenic transformation, progression, and chemoresistance across many cancers, establishing it as an attractive therapeutic target. Over the last several decades, significant efforts have been made to inhibit eIF4E through the development of mechanistically distinct small-molecule inhibitors that both directly and indirectly act on eIF4E to prevent cap-dependent translation initiation. These inhibitors can serve as powerful chemical tools to improve our understanding of the mechanisms of cap-dependent translation in cancer and to ultimately predict specific cancers that may benefit from eIF4E-targeted therapeutics. This review discusses the progress made in the development of different classes of small-molecule eIF4E inhibitors, the challenges that remain, and their potential as chemical probes to elucidate the complexities of cap-dependent translation in cancer.
Insights
Cancer cells hijack protein production by overexpressing eukaryotic translation initiation factor 4E (eIF4E). Small-molecule inhibitors targeting eIF4E offer a promising therapeutic strategy for various cancers.
Area of Science:
- Molecular Biology
- Oncology
- Biochemistry
Background:
- Dysregulated translation is a key feature of cancer, enabling proteome alterations that promote tumor survival.
- Key signaling pathways (PI3K-AKT-mTORC1, RAS-RAF-MAPK, MYC) converge on eukaryotic translation initiation factor 4E (eIF4E), a critical regulator of cap-dependent translation.
- eIF4E overexpression drives oncogenic transformation, progression, and chemoresistance, making it a significant therapeutic target.
Purpose of the Study:
- To review the development of small-molecule inhibitors targeting eIF4E.
- To discuss the challenges and potential of eIF4E inhibitors in cancer therapy.
- To highlight the use of these inhibitors as chemical probes for understanding translation in cancer.
Main Methods:
- Review of literature on small-molecule eIF4E inhibitors.
- Analysis of mechanisms of direct and indirect eIF4E inhibition.
- Discussion of the role of eIF4E in cancer and therapeutic strategies.
Main Results:
- Significant progress has been made in developing diverse classes of small-molecule eIF4E inhibitors.
- These inhibitors directly or indirectly target eIF4E to block cap-dependent translation initiation.
- eIF4E inhibitors show potential as therapeutic agents and research tools.
Conclusions:
- Small-molecule inhibitors targeting eIF4E represent a promising therapeutic avenue for cancer.
- Further research is needed to overcome challenges and optimize eIF4E-targeted therapies.
- These inhibitors can advance our understanding of translational control in oncogenesis.
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