Chemical Probes for Studying the Eukaryotic Translation Initiation Factor 4E (eIF4E)-Regulated Translatome in Cancer.

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 mGpppX 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.