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A TRIM21-based bioPROTAC highlights the therapeutic benefit of HuR degradation

Author

Listed:
  • Alice Fletcher

    (R&D, AstraZeneca)

  • Dean Clift

    (Francis Crick Avenue, Cambridge Biomedical Campus)

  • Emma Vries

    (R&D, AstraZeneca)

  • Sergio Martinez Cuesta

    (Discovery Sciences, R&D, AstraZeneca)

  • Timothy Malcolm

    (R&D, AstraZeneca)

  • Francesco Meghini

    (R&D, AstraZeneca)

  • Raghothama Chaerkady

    (Discovery Sciences, R&D, AstraZeneca)

  • Junmin Wang

    (Discovery Sciences, R&D, AstraZeneca)

  • Abby Chiang

    (Discovery Sciences, R&D, AstraZeneca)

  • Shao Huan Samuel Weng

    (Discovery Sciences, R&D, AstraZeneca)

  • Jonathan Tart

    (Discovery Sciences, R&D, AstraZeneca)

  • Edmond Wong

    (R&D, AstraZeneca)

  • Gerard Donohoe

    (R&D, AstraZeneca)

  • Philip Rawlins

    (Discovery Sciences, R&D, AstraZeneca)

  • Euan Gordon

    (Discovery Sciences, R&D, AstraZeneca)

  • Jonathan D. Taylor

    (R&D, AstraZeneca)

  • Leo James

    (Francis Crick Avenue, Cambridge Biomedical Campus)

  • James Hunt

    (R&D, AstraZeneca)

Abstract

Human antigen R (HuR) is a ubiquitously expressed RNA-binding protein, which functions as an RNA regulator. Overexpression of HuR correlates with high grade tumours and poor patient prognosis, implicating it as an attractive therapeutic target. However, an effective small molecule antagonist to HuR for clinical use remains elusive. Here, a single domain antibody (VHH) that binds HuR with low nanomolar affinity was identified and shown to inhibit HuR binding to RNA. This VHH was used to engineer a TRIM21-based biological PROTAC (bioPROTAC) that could degrade endogenous HuR. Significantly, HuR degradation reverses the tumour-promoting properties of cancer cells in vivo by altering the HuR-regulated proteome, highlighting the benefit of HuR degradation and paving the way for the development of HuR-degrading therapeutics. These observations have broader implications for degrading intractable therapeutic targets, with bioPROTACs presenting a unique opportunity to explore targeted-protein degradation through a modular approach.

Suggested Citation

  • Alice Fletcher & Dean Clift & Emma Vries & Sergio Martinez Cuesta & Timothy Malcolm & Francesco Meghini & Raghothama Chaerkady & Junmin Wang & Abby Chiang & Shao Huan Samuel Weng & Jonathan Tart & Edm, 2023. "A TRIM21-based bioPROTAC highlights the therapeutic benefit of HuR degradation," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42546-2
    DOI: 10.1038/s41467-023-42546-2
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    References listed on IDEAS

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    1. Florian Meier & Niklas D. Köhler & Andreas-David Brunner & Jean-Marc H. Wanka & Eugenia Voytik & Maximilian T. Strauss & Fabian J. Theis & Matthias Mann, 2021. "Deep learning the collisional cross sections of the peptide universe from a million experimental values," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
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