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.
Authors
- Klára Dohnalová
- Karel Chalupský (ORCID: https://orcid.org/0000-0001-6890-6464)
- Radim Nencka (ORCID: https://orcid.org/0000-0001-6167-0380)
- Rajamanikkam Kamaraj (ORCID: https://orcid.org/0000-0001-7115-0178)
- Petr Pávek (ORCID: https://orcid.org/0000-0001-8769-4196)
- Lucie Smutná (ORCID: https://orcid.org/0000-0002-3941-4193)
- Markus F. Templin (ORCID: https://orcid.org/0000-0002-6569-6489)
- Ivana Mejdrová (ORCID: https://orcid.org/0009-0007-1587-9811)
- Tomáš Smutný (ORCID: https://orcid.org/0000-0001-5788-7413)
- Jana Hricová (ORCID: https://orcid.org/0009-0008-9369-8853)
- Aaron Stahl (ORCID: https://orcid.org/0000-0003-3616-9564)
- Thales Kronenberger (ORCID: https://orcid.org/0000-0001-6933-7590)
- Kryštof Škach (ORCID: https://orcid.org/0000-0002-7558-6961)
- Albert Braeuning (ORCID: https://orcid.org/0000-0003-3810-027X)
- Ján Dušek (ORCID: https://orcid.org/0000-0002-1946-4994)
- Mária Krutáková
- Dharani Sai Sreekanth Nellore
Institutions
- Charles University (CZ)
- Federal Institute for Risk Assessment (DE)
- Natural and Medical Sciences Institute (DE)
- German Center for Infection Research (DE)
- University Children's Hospital Tübingen (DE)
- Czech Academy of Sciences, Institute of Molecular Genetics (CZ)
- Czech Academy of Sciences, Institute of Organic Chemistry and Biochemistry (CZ)
- University of Hradec Králové (CZ)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-07-12
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c03134
- Citations
- 5
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 4.03
Funders
- Grantová Agentura, Univerzita Karlova
- Deutsches Zentrum für Infektionsforschung
- European Commission
- Ministerstvo Školství, Mládeže a Tělovýchovy
- Grantová Agentura České Republiky