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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 & , 2024. "Integrating fragment-based screening with targeted protein degradation and genetic rescue to explore eIF4E function," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54356-1
    DOI: 10.1038/s41467-024-54356-1
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    References listed on IDEAS

    as
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