糖皮质激素受体
蛋白质水解
体内
受体
糖皮质激素
化学
计算生物学
细胞生物学
药理学
生物
生物化学
内分泌学
酶
遗传学
作者
Mahshid Gazorpak,Karina M. Hugentobler,Dominique Paul,Pierre-Luc Germain,Miriam Kretschmer,Iryna Ivanova,Stefan Frei,Kei Mathis,Remo Rudolf,Sergio Mompart Barrenechea,V. Fischer,Xiaohan Xue,Aleksandra L. Ptaszek,Julian Holzinger,Mattia Privitera,Andreas Hierlemann,Onno C. Meijer,Robert Konrat,Erick M. Carreira,Johannes Bohacek,Katharina Gapp
标识
DOI:10.1038/s41467-023-44031-2
摘要
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.
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