Harnessing PROTAC technology to combat stress hormone receptor activation

Gazorpak, M.; Hungentobler, K. M.; Dominique, P.; Germain, P.-L.; Mathis, K.; Rudolf, R.; Barrenechea, S. M.; Kretschmer, M.; Fischer, V. V.; Xue, X.; Privitera, M.; Ivanova, I.; Hierlemann, A.; Meijer, O. C.; Carreira, E. M.; Bohacek, J.; Gapp, K.

doi:10.1101/2023.03.17.533120

bioRxiv · 10.1101/2023.03.17.533120

Harnessing PROTAC technology to combat stress hormone receptor activation

Gazorpak, M.·Hungentobler, K. M.·Dominique, P.·Germain, P.-L.·Mathis, K.·Rudolf, R.·Barrenechea, S. M.·Kretschmer, M.·Fischer, V. V.·Xue, X.·Privitera, M.·Ivanova, I.·Hierlemann, A.·Meijer, O. C.·Carreira, E. M.·Bohacek, J.·Gapp, K.

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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, novel 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 GRs 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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Gazorpak, M., Hungentobler, K. M., Dominique, P., Germain, P.-L., Mathis, K., Rudolf, R., Barrenechea, S. M., Kretschmer, M., Fischer, V. V., Xue, X., Privitera, M., Ivanova, I., Hierlemann, A., Meijer, O. C., Carreira, E. M., Bohacek, J., Gapp, K.. 2023-03-18. Harnessing PROTAC technology to combat stress hormone receptor activation. https://doi.org/10.1101/2023.03.17.533120

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