Discovery of PXR Antagonist MI891 and PXR Degrader MI1013 and Their Roles in Hepatic Gene Regulation

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,
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 human hepatocytes. Our findings
indicate that PXR antagonism or degradation suppresses basal and rifampicin-induced
expression of selected ADME genes. Moreover, the PXR antagonists and
PROTAC degrader downregulate the expression of several key genes involved
in gluconeogenesis, cholesterol homeostasis, bile acid synthesis,
and proliferation in hepatocyte cells, suggesting their potential
therapeutic applications for metabolic diseases.