1区 · 综合性期刊
ArticleOA
作者: Gazorpak, Mahshid ; Fischer, Vincent ; Ptaszek, Aleksandra L ; Gapp, Katharina ; Mathis, Kei ; Bohacek, Johannes ; Ivanova, Iryna ; Privitera, Mattia ; Kretschmer, Miriam ; Rudolf, Remo ; Frei, Selina ; Germain, Pierre-Luc ; Hierlemann, Andreas ; Meijer, Onno C ; Holzinger, Julian ; Konrat, Robert ; Mompart Barrenechea, Sergio ; Paul, Dominique ; Xue, Xiaohan ; Hugentobler, Karina M ; Carreira, Erick M
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.
