Figure 6
From: Allosteric modulation of the farnesoid X receptor by a small molecule
In vitro profiling of FXR modulator 16. (A) At 10 µM, 16 significantly enhances transactivation efficacy of FXR agonists 1–3 in a full-length FXR reporter gene assay. (B) Dose-response curves of FXR agonist 1 and compound 16 in presence of a fixed concentration of the respective other agent confirms increased maximum relative transactivation without marked changes in EC50-values. The maximum relative transactivation exceeds the sum of the single compounds’ maximum relative transactivation suggesting synergy. (C) 16 does not activate FXR’s heterodimer partner RXR. (D) 16 is a potent inhibitor of the kinases Abl, c-Kit and PDGF-Rα but does not markedly inhibit kinases that interact with FXR. (E) 16 is less cytotoxic than 4. (F) 16 possesses higher microsomal stability than 4. (G) 16 is highly selective over nuclear receptors related to FXR. (H) 16 does not modulate the membrane bile acid receptor TGR5. *p < 0.05, **p < 0.01, ***p < 0.001.
