| Title: |
Integrating fragment-based screening with targeted protein degradation and genetic rescue to explore eIF4E function. |
| Authors: |
Sharp, SY; Martella, M; D'Agostino, S; Milton, CI; Ward, G; Woodhead, AJ; Richardson, CJ; Carr, MG; Chiarparin, E; Cons, BD; Coyle, J; East, CE; Hiscock, SD; Martinez-Fleites, C; Mortenson, PN; Palmer, N; Pathuri, P; Powers, MV; Saalau, SM; St Denis, JD; Swabey, K; Vinković, M; Walton, H; Williams, G; Clarke, PA |
| Contributors: |
Powers, Marissa; Clarke, Paul |
| Publisher Information: |
NATURE PORTFOLIO |
| Publication Year: |
2025 |
| Collection: |
The Institute of Cancer Research (ICR): Publications Repository |
| Subject Terms: |
Eukaryotic Initiation Factor-4E; Humans; Eukaryotic Initiation Factor-4G; Binding Sites; Proteolysis; Protein Binding; Protein Biosynthesis; HEK293 Cells; Drug Discovery; Small Molecule Libraries; Ligands |
| Subject Geographic: |
England |
| Description: |
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, Kd = 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 (EC50 = 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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
Electronic; application/pdf |
| Language: |
English |
| ISSN: |
2041-1723 |
| Relation: |
ARTN 10037; Nature Communications, 2024, 15 (1), pp. 10037 -; https://repository.icr.ac.uk/handle/internal/6790 |
| Availability: |
https://repository.icr.ac.uk/handle/internal/6790 |
| Rights: |
http://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.B9FED592 |
| Database: |
BASE |