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Harnessing PROTAC technology to combat stress hormone receptor activation

Author

Listed:
  • Mahshid Gazorpak

    (ETH Zürich
    ETH Zürich and University of Zürich)

  • Karina M. Hugentobler

    (ETH Zürich)

  • Dominique Paul

    (University of Zürich)

  • Pierre-Luc Germain

    (ETH Zürich
    University of Zürich
    ETH Zürich)

  • Miriam Kretschmer

    (ETH Zürich
    ETH Zürich and University of Zürich)

  • Iryna Ivanova

    (ETH Zürich)

  • Selina Frei

    (ETH Zürich)

  • Kei Mathis

    (ETH Zürich)

  • Remo Rudolf

    (ETH Zürich)

  • Sergio Mompart Barrenechea

    (ETH Zürich)

  • Vincent Fischer

    (ETH Zürich
    ETH Zürich and University of Zürich)

  • Xiaohan Xue

    (ETH Zürich)

  • Aleksandra L. Ptaszek

    (University of Vienna)

  • Julian Holzinger

    (University of Vienna)

  • Mattia Privitera

    (ETH Zürich)

  • Andreas Hierlemann

    (ETH Zürich)

  • Onno C. Meijer

    (Leiden University Medical Center)

  • Robert Konrat

    (University of Vienna)

  • Erick M. Carreira

    (ETH Zürich)

  • Johannes Bohacek

    (ETH Zürich and University of Zürich
    ETH Zürich)

  • Katharina Gapp

    (ETH Zürich
    ETH Zürich and University of Zürich)

Abstract

Counteracting the overactivation of glucocorticoid receptors (GR) is an important therapeutic goal in stress-related psychiatry and beyond. The only clinically approved GR antagonist lacks selectivity and induces unwanted side effects. To complement existing tools of small-molecule-based inhibitors, we present a highly potent, catalytically-driven GR degrader, KH-103, based on proteolysis-targeting chimera technology. This selective degrader enables immediate and reversible GR depletion that is independent of genetic manipulation and circumvents transcriptional adaptations to inhibition. KH-103 achieves passive inhibition, preventing agonistic induction of gene expression, and significantly averts the GR’s genomic effects compared to two currently available inhibitors. Application in primary-neuron cultures revealed the dependency of a glucocorticoid-induced increase in spontaneous calcium activity on GR. Finally, we present a proof of concept for application in vivo. KH-103 opens opportunities for a more lucid interpretation of GR functions with translational potential.

Suggested Citation

  • Mahshid Gazorpak & Karina M. Hugentobler & Dominique Paul & Pierre-Luc Germain & Miriam Kretschmer & Iryna Ivanova & Selina Frei & Kei Mathis & Remo Rudolf & Sergio Mompart Barrenechea & Vincent Fisch, 2023. "Harnessing PROTAC technology to combat stress hormone receptor activation," Nature Communications, Nature, vol. 14(1), pages 1-23, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-44031-2
    DOI: 10.1038/s41467-023-44031-2
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    References listed on IDEAS

    as
    1. Behnam Nabet & Fleur M. Ferguson & Bo Kyung A. Seong & Miljan Kuljanin & Alan L. Leggett & Mikaela L. Mohardt & Amanda Robichaud & Amy S. Conway & Dennis L. Buckley & Joseph D. Mancias & James E. Brad, 2020. "Rapid and direct control of target protein levels with VHL-recruiting dTAG molecules," Nature Communications, Nature, vol. 11(1), pages 1-8, December.
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