TY  - JOUR
A1  - Gabler, Matthias
A1  - Kramer, Jan
A1  - Schmidt, Jurema
A1  - Pollinger, Julius
A1  - Weber, Julia
A1  - Kaiser, Astrid
A1  - Löhr, Frank
A1  - Proschak, Ewgenij
A1  - Schubert-Zsilavecz, Manfred
A1  - Merk, Daniel
T1  - Allosteric modulation of the farnesoid X receptor by a small molecule
T2  - Scientific reports
N2  - 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.
KW  - Pharmacodynamics
KW  - Target validation
Y1  - 2018
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/47225
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-472257
SN  - 2045-2322
N1  - 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/.
VL  - 8
IS  - 1, Art. 6846
SP  - 1
EP  - 11
PB  - Macmillan Publishers Limited, part of Springer Nature
CY  - [London]
ER  -