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Structural insights into human brachyury DNA recognition and discovery of progressible binders for cancer therapy

Author

Listed:
  • Joseph A. Newman

    (University of Oxford)

  • Angeline E. Gavard

    (University of Oxford
    Exscientia)

  • Nergis Imprachim

    (University of Oxford
    University of Cambridge)

  • Hazel Aitkenhead

    (University of Oxford
    Diamond Light Source Ltd)

  • Hadley E. Sheppard

    (The Institute of Cancer Research
    Sano Genetics Ltd)

  • Robert Poele

    (The Institute of Cancer Research)

  • Paul A. Clarke

    (The Institute of Cancer Research)

  • Mohammad Anwar Hossain

    (University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill)

  • Louisa Temme

    (University of North Carolina at Chapel Hill
    University of Hamburg)

  • Hans J. Oh

    (University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill)

  • Carrow I. Wells

    (University of North Carolina at Chapel Hill
    GlaxoSmithKline)

  • Zachary W. Davis-Gilbert

    (University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill)

  • Paul Workman

    (The Institute of Cancer Research)

  • Opher Gileadi

    (University of Oxford
    Centre for Molecular Medicine)

  • David H. Drewry

    (University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill)

Abstract

Brachyury is a transcription factor that plays an essential role in tumour growth of the rare bone cancer chordoma and is implicated in other solid tumours. Brachyury is minimally expressed in healthy tissues, making it a potential therapeutic target. Unfortunately, as a ligandless transcription factor, brachyury has historically been considered undruggable. To investigate direct targeting of brachyury by small molecules, we determine the structure of human brachyury both alone and in complex with DNA. The structures provide insights into DNA binding and the context of the chordoma associated G177D variant. We use crystallographic fragment screening to identify hotspots on numerous pockets on the brachyury surface. Finally, we perform follow-up chemistry on fragment hits and describe the progression of a thiazole chemical series into binders with low µM potency. Thus we show that brachyury is ligandable and provide an example of how crystallographic fragment screening may be used to target protein classes that are difficult to address using other approaches.

Suggested Citation

  • Joseph A. Newman & Angeline E. Gavard & Nergis Imprachim & Hazel Aitkenhead & Hadley E. Sheppard & Robert Poele & Paul A. Clarke & Mohammad Anwar Hossain & Louisa Temme & Hans J. Oh & Carrow I. Wells , 2025. "Structural insights into human brachyury DNA recognition and discovery of progressible binders for cancer therapy," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56213-1
    DOI: 10.1038/s41467-025-56213-1
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    References listed on IDEAS

    as
    1. Christoph W. Müller & Bernhard G. Herrmann, 1997. "Crystallographic structure of the T domain–DNA complex of the Brachyury transcription factor," Nature, Nature, vol. 389(6653), pages 884-888, October.
    2. Nicholas M. Pearce & Tobias Krojer & Anthony R. Bradley & Patrick Collins & Radosław P. Nowak & Romain Talon & Brian D. Marsden & Sebastian Kelm & Jiye Shi & Charlotte M. Deane & Frank von Delft, 2017. "A multi-crystal method for extracting obscured crystallographic states from conventionally uninterpretable electron density," Nature Communications, Nature, vol. 8(1), pages 1-8, April.
    3. Patrick S. Tarpey & Sam Behjati & Matthew D. Young & Inigo Martincorena & Ludmil B. Alexandrov & Sarah J. Farndon & Charlotte Guzzo & Claire Hardy & Calli Latimer & Adam P. Butler & Jon W. Teague & Ad, 2017. "The driver landscape of sporadic chordoma," Nature Communications, Nature, vol. 8(1), pages 1-6, December.
    Full references (including those not matched with items on IDEAS)

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