Allosteric modulation of the farnesoid X receptor by a small molecule

  • The bile acid activated transcription factor farnesoid X receptor (FXR) regulates numerous metabolic processes and is a rising target for the treatment of hepatic and metabolic disorders. FXR agonists have revealed efficacy in treating non-alcoholic steatohepatitis (NASH), diabetes and dyslipidemia. Here we characterize imatinib as first-in-class allosteric FXR modulator and report the development of an optimized descendant that markedly promotes agonist induced FXR activation in a reporter gene assay and FXR target gene expression in HepG2 cells. Differential effects of imatinib on agonist-induced bile salt export protein and small heterodimer partner expression suggest that allosteric FXR modulation could open a new avenue to gene-selective FXR modulators.

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Author:Matthias Gabler, Jan Kramer, Jurema SchmidtGND, Julius Pollinger, Julia Weber, Astrid Kaiser, Frank LöhrORCiD, Ewgenij ProschakORCiDGND, Manfred Schubert-ZsilaveczGND, Daniel MerkORCiDGND
URN:urn:nbn:de:hebis:30:3-472257
DOI:https://doi.org/10.1038/s41598-018-25158-5
ISSN:2045-2322
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/29717168
Parent Title (English):Scientific reports
Publisher:Macmillan Publishers Limited, part of Springer Nature
Place of publication:[London]
Document Type:Article
Language:English
Year of Completion:2018
Date of first Publication:2018/05/01
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2018/08/14
Tag:Pharmacodynamics; Target validation
Volume:8
Issue:1, Art. 6846
Page Number:11
First Page:1
Last Page:11
Note:
Rights and permissions: Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
HeBIS-PPN:450868958
Institutes:Biochemie, Chemie und Pharmazie / Biochemie und Chemie
Biochemie, Chemie und Pharmazie / Pharmazie
Wissenschaftliche Zentren und koordinierte Programme / Zentrum für Biomolekulare Magnetische Resonanz (BMRZ)
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Open-Access-Publikationsfonds:Biochemie, Chemie und Pharmazie
Licence (German):License LogoCreative Commons - Namensnennung 4.0