학술논문
Harnessing PROTAC technology to combat stress hormone receptor activation
Document Type
article
Author
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; Katharina Gapp
Source
Nature Communications, Vol 14, Iss 1, Pp 1-23 (2023)
Subject
Language
English
ISSN
2041-1723
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.