Identification of FDA-approved drugs targeting the Farnesoid X Receptor
| Autor: | Sandra M. W. van de Wiel, Saskia W.C. van Mil, Stan F.J. van de Graaf, Ingrid T. G. W. Bijsmans |
|---|---|
| Přispěvatelé: | Tytgat Institute for Liver and Intestinal Research, AGEM - Endocrinology, metabolism and nutrition, Graduate School, ACS - Atherosclerosis & ischemic syndromes |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Receptors Cytoplasmic and Nuclear lcsh:Medicine Biosensing Techniques Pharmacology Ligands Article Cell Line Bile Acids and Salts 03 medical and health sciences 0302 clinical medicine Fluorescence Resonance Energy Transfer Journal Article medicine Humans RNA Messenger lcsh:Science Receptor Drug Approval Ivermectin Multidisciplinary Molecular Structure United States Food and Drug Administration Chemistry Multidrug resistance-associated protein 2 lcsh:R Drug Repositioning FGF19 Isoxazoles United States High-Throughput Screening Assays 3. Good health Drug repositioning 030104 developmental biology Nuclear receptor Bepridil lcsh:Q Farnesoid X receptor 030217 neurology & neurosurgery Gliquidone medicine.drug |
| Zdroj: | Scientific reports, 9(1):2193. Nature Publishing Group Scientific Reports, 9(1), 2193. Nature Publishing Group Scientific Reports, Vol 9, Iss 1, Pp 1-11 (2019) Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | The farnesoid X receptor (FXR) belongs to the nuclear receptor family and is activated by bile acids. Multiple, chemically rather diverse, FXR agonists have been developed and several of these compounds are currently tested in clinical trials for NAFLD and cholestasis. Here, we investigated possible FXR-agonism or antagonism of existing FDA/EMA-approved drugs. By using our recently developed FRET-sensor, containing the ligand binding domain of FXR (FXR-LBD), 1280 FDA-approved drugs were screened for their ability to activate FXR in living cells using flow cytometry. Fifteen compounds induced the sensor for more than twenty percent above background. Real-time confocal microscopy confirmed that avermectin B1a, gliquidone, nicardipine, bepridil and triclosan activated the FRET sensor within two minutes. These compounds, including fluticasone, increased mRNA expression of FXR target genes OSTα and OSTβ in Huh7 cells, and in most cases also of MRP2, SHP and FGF19. Finally, avermectin B1a, gliquidone, nicardipine and bepridil significantly increased IBABP promoter activity in a luciferase reporter assay in a dose-dependent manner. In conclusion, six FDA/EMA-approved drugs currently used in the clinical practice exhibit moderate agonistic FXR activity. This may on the one hand explain (undesired) side-effects, but on the other hand may form an opportunity for polypharmacology. |
| Databáze: | OpenAIRE |
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