2024/11/20 by Swee Y. Sharp, Marianna Martella, Sabrina D’Agostino +22 · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · #Monoclonal and Polyclonal Antibodies Research #PI3K/AKT/mTOR signaling in cancer #Protein Degradation and Inhibitors
paper · pdf · doi:10.1038/s41467-024-54356-1
openalex publication_date 2024/11/20 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/03
Abstract Eukaryotic initiation factor 4E (eIF4E) serves as a regulatory hub for oncogene-driven protein synthesis and is considered a promising anticancer target. Here we screen a fragment library against eIF4E and identify a ligand-binding site with previously unknown function. Follow-up structure-based design yields a low nM tool compound ( 4 , K d = 0.09 µM; LE 0.38), which disrupts the eIF4E:eIF4G interaction, inhibits translation in cell lysates, and demonstrates target engagement with eIF4E in intact cells (EC 50 = 2 µM). By coupling targeted protein degradation with genetic rescue using eIF4E mutants, we show that disruption of both the canonical eIF4G and non-canonical binding sites is likely required to drive a strong cellular effect. This work highlights the power of fragment-based drug discovery to identify pockets in difficult-to-drug proteins and how this approach can be combined with genetic characterization and degrader technology to probe protein function in complex biological systems.