Integrating fragment-based screening with targeted protein degradation and genetic rescue to explore eIF4E function

Swee Y. Sharp, Marianna Martella, Sabrina D’Agostino, Christopher I. Milton, George Ward, Andrew J. Woodhead (), Caroline J. Richardson (), Maria G. Carr, Elisabetta Chiarparin, Benjamin D. Cons, Joseph Coyle, Charlotte E. East, Steven D. Hiscock, Carlos Martinez-Fleites, Paul N. Mortenson, Nick Palmer, Puja Pathuri, Marissa V. Powers, Susanne M. Saalau, Jeffrey D. Denis, Kate Swabey, Mladen Vinković, Hugh Walton, Glyn Williams and Paul A. Clarke ()
Additional contact information
Swee Y. Sharp: Institute of Cancer Research
Marianna Martella: Institute of Cancer Research
Sabrina D’Agostino: Institute of Cancer Research
Christopher I. Milton: Institute of Cancer Research
George Ward: Cambridge Science Park
Andrew J. Woodhead: Cambridge Science Park
Caroline J. Richardson: Cambridge Science Park
Maria G. Carr: Cambridge Science Park
Elisabetta Chiarparin: Cambridge Science Park
Benjamin D. Cons: Cambridge Science Park
Joseph Coyle: Cambridge Science Park
Charlotte E. East: Cambridge Science Park
Steven D. Hiscock: Cambridge Science Park
Carlos Martinez-Fleites: Cambridge Science Park
Paul N. Mortenson: Cambridge Science Park
Nick Palmer: Cambridge Science Park
Puja Pathuri: Cambridge Science Park
Marissa V. Powers: Institute of Cancer Research
Susanne M. Saalau: Cambridge Science Park
Jeffrey D. Denis: Cambridge Science Park
Kate Swabey: Institute of Cancer Research
Mladen Vinković: Cambridge Science Park
Hugh Walton: Cambridge Science Park
Glyn Williams: Cambridge Science Park
Paul A. Clarke: Institute of Cancer Research

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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, 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.

Date: 2024
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DOI: 10.1038/s41467-024-54356-1

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