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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F25%3A00637607" target="_blank" >RIV/61388963:_____/25:00637607 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/68378050:_____/25:00637607 RIV/00216208:11110/25:10505626 RIV/00216208:11160/25:10505626 RIV/60461373:22330/25:43932004

Výsledek na webu

<a href="https://doi.org/10.1021/acs.jmedchem.4c03134" target="_blank" >https://doi.org/10.1021/acs.jmedchem.4c03134</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acs.jmedchem.4c03134" target="_blank" >10.1021/acs.jmedchem.4c03134</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

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OECD FORD obor

30107 - Medicinal chemistry

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Journal of Medicinal Chemistry

ISSN

0022-2623

e-ISSN

1520-4804

Svazek periodika

68

Číslo periodika v rámci svazku

14

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

29

Strana od-do

14271-14299

Kód UT WoS článku

001527357600001

EID výsledku v databázi Scopus

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