Harnessing PROTAC technology to combat stress hormone receptor activation
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Published:2023-12-09
Issue:1
Volume:14
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Gazorpak MahshidORCID, Hugentobler Karina M.ORCID, Paul Dominique, Germain Pierre-LucORCID, Kretschmer MiriamORCID, Ivanova IrynaORCID, Frei Selina, Mathis KeiORCID, Rudolf RemoORCID, Mompart Barrenechea SergioORCID, Fischer VincentORCID, Xue XiaohanORCID, Ptaszek Aleksandra L.ORCID, Holzinger JulianORCID, Privitera MattiaORCID, Hierlemann AndreasORCID, Meijer Onno C.ORCID, Konrat Robert, Carreira Erick M., Bohacek JohannesORCID, Gapp KatharinaORCID
Abstract
AbstractCounteracting 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.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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