Harnessing PROTAC technology to combat stress hormone receptor activation

Mahshid Gazorpak, Karina M. Hugentobler, Dominique Paul, Pierre-Luc Germain, Miriam Kretschmer, Iryna Ivanova, Selina Frei, Kei Mathis, Remo Rudolf, Sergio Mompart Barrenechea, Vincent Fischer, Xiaohan Xue, Aleksandra L. Ptaszek, Julian Holzinger, Mattia Privitera, Andreas Hierlemann, Onno C. Meijer, Robert Konrat, Erick M. Carreira, Johannes Bohacek and Katharina Gapp ()
Additional contact information
Mahshid Gazorpak: ETH Zürich
Karina M. Hugentobler: ETH Zürich
Dominique Paul: University of Zürich
Pierre-Luc Germain: ETH Zürich
Miriam Kretschmer: ETH 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
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
Katharina Gapp: ETH Zürich

Nature Communications, 2023, vol. 14, issue 1, 1-23

Abstract: 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.

Date: 2023
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-44031-2

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DOI: 10.1038/s41467-023-44031-2

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