2. Academic Validation
  3. Discovery of PXR Antagonist MI891 and PXR Degrader MI1013 and Their Roles in Hepatic Gene Regulation

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

  • J Med Chem. 2025 Jul 24;68(14):14271-14299. doi: 10.1021/acs.jmedchem.4c03134.
Rajamanikkam Kamaraj 1,  Ivana Mejdrová 2,  Maria Krutakova 1,  Tomas Smutny 1,  Kryštof Škach 2,  Klara Dohnalova 3 4,  Lucie Smutna 1,  Dharani Sai Sreekanth Nellore 1,  Jan Dusek 1,  Karel Chalupsky 3,  Jana Hricová 2,  Thales Kronenberger 5,  Aaron Stahl 6,  Markus Templin 6,  Albert Braeuning 7,  Radim Nencka 2,  Petr Pavek 1
Affiliations

Affiliations

  • 1 Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic.
  • 2 Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
  • 3 Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic.
  • 4 First Faculty of Medicine, Charles University, Katerinska 32, 112 08 Prague, Czech Republic.
  • 5 DZIF Tübingen Partner Site, University Hospital Tübingen, 72076 Tuebingen, Germany.
  • 6 NMI - Natural and Medical Sciences Institute at the University of Tuebingen, Markwiesenstr. 55, 72770 Reutlingen, Germany.
  • 7 Department Food Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, Berlin 10589, Germany.
PMID: 40650588 DOI: 10.1021/acs.jmedchem.4c03134
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.

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