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.
Highlights
Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily predominantly found in liver, intestine and kidney[1,2,3,4]
Since 4 still possesses high therapeutic relevance in the treatment of chronic myeloid leukemia (CML) such side activity seems important especially because it might be connected to anti-diabetic effects that were observed under treatment with 413–15
Initial dose-response evaluation of 4 in a full-length farnesoid X receptor (FXR) transactivation assay revealed an EC50-value of 6.6 ± 0.3 μM with a relative maximum activation of 10.7 ± 0.1% compared to FXR full agonist 3 (3 μM) indicating that 4 has partial FXR agonistic activity
Summary
Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily predominantly found in liver, intestine and kidney[1,2,3,4]. FXR activity can be modulated by phosphorylation and since 4 is a potent kinase inhibitor, kinase-mediated effects may affect transactivation of the FXR/RXR heterodimer in our reporter gene assay.
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