Speaker
Description
The pregnane X receptor (PXR) is an important regulator of hepatic metabolism, yet mechanistic insights into the effects of pharmacological inhibition using PXR inverse agonists or antagonists on critical genes involved in both xenobiotic and endobiotic metabolism remain limited.
Here, we discovered a novel PXR inverse agonist/antagonist, MI891, which binds to the ligand-binding domain of PXR. Furthermore, we computationally designed and synthesized the proteolysis-targeting chimera molecule (PROTAC), MI1013, based on the PXR antagonist SPA70, which degrades PXR in HepaRG hepatic cells. Using these tools, we investigated the regulation of key PXR target genes in HepaRG cells and primary human hepatocytes.
Our findings indicate that PXR antagonism or degradation suppresses basal and rifampicin-induced expression of selected ADME genes in differentiated HepaRG cells. Moreover, PXR antagonists and PROTAC degraders downregulate the expression of several key genes involved in gluconeogenesis, cholesterol homeostasis, bile acid synthesis, and hepatocyte proliferation, suggesting their potential therapeutic applications for metabolic diseases.
Acknowledgments:
The project New Technologies for Translational Research in Pharmaceutical Sciences (NETPHARM), project ID CZ.02.01.01/00/22_008/0004607, is co-funded by the European Union.
