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Discovery of PXR Antagonist MI891 and PXR Degrader MI1013 and Their Roles in Hepatic Gene Regulation
Rajamanikkam Kamaraj1, Ivana Mejdrová2, Maria Krutakova1
1Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic.
Abstract:
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.
Insights
Researchers identified novel compounds that inhibit or degrade the pregnane X receptor (PXR). This PXR inhibition impacts genes in drug metabolism and metabolic diseases, offering potential therapeutic avenues.
Area of Science:
- Pharmacology
- Hepatology
- Molecular Biology
Background:
- The pregnane X receptor (PXR) is a key regulator of hepatic metabolism for both endogenous and exogenous compounds.
- Limited mechanistic understanding exists regarding the impact of PXR inhibition on critical metabolic genes.
Purpose of the Study:
- To discover and characterize novel PXR inverse agonists/antagonists.
- To investigate the effects of PXR inhibition and degradation on PXR target genes in liver cells.
Main Methods:
- Discovery of a novel PXR inverse agonist/antagonist (MI891).
- Computational design and synthesis of a PXR-targeting PROTAC degrader (MI1013).
- Assessment of gene expression in HepaRG cells and human hepatocytes.
Main Results:
- MI891 binds to the PXR ligand-binding domain.
- MI1013 effectively degrades PXR in HepaRG cells.
- PXR antagonism and degradation suppressed basal and induced expression of ADME genes.
- Inhibition/degradation of PXR downregulated genes involved in gluconeogenesis, cholesterol homeostasis, bile acid synthesis, and cell proliferation.
Conclusions:
- Novel PXR antagonists and a PROTAC degrader were developed.
- Pharmacological PXR inhibition/degradation impacts key metabolic pathways in hepatocytes.
- These findings suggest potential therapeutic applications for PXR modulators in metabolic diseases.
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