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Allosteric modulation of the farnesoid X receptor by a small molecule.

ABSTRACT: 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.

SUBMITTER: Gabler M

PROVIDER: S-EPMC5931576 | biostudies-other | 2018 May

REPOSITORIES: biostudies-other

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Allosteric modulation of the farnesoid X receptor by a small molecule.

Gabler Matthias M Kramer Jan J Schmidt Jurema J Pollinger Julius J Weber Julia J Kaiser Astrid A Löhr Frank F Proschak Ewgenij E Schubert-Zsilavecz Manfred M Merk Daniel D

Scientific reports 20180501 1

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 ...[more]

PMID: 29717168

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