Repositioning an Immunomodulatory Drug Vidofludimus as a Farnesoid X Receptor Modulator With Therapeutic Effects on NAFLD

Abstract

Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disorder, and yet with no pharmacological treatment approved worldwide. The repositioning of old drugs provides a safe approach for drug development. Vidofludimus, an inhibitor for dihydroorotate dehydrogenase (DHODH) for the treatment of autoimmune disorders, is herein uncovered as a novel modulator for farnesoid X receptor (FXR) by biochemical and crystallographic analysis. We further revealed that vidofludimus exerts in vivo therapeutic effects on dextran sodium sulfate (DSS)-induced colitis in an FXR-dependent manner. Notably, vidofludimus also possesses remarkable beneficial effects in reducing NAFLD by targeting FXR, which may represent a unique approach in developing the treatment for NAFLD. Our findings not only reveal a promising template for the design of novel FXR ligands in treating autoimmune disorders, but also uncover a novel therapeutic effect for vidofludimus on NAFLD based on the newly established relationships among drugs, targets, and diseases.

Recent Advances in the Medicinal Chemistry of Farnesoid X Receptor

“…Vidofludimus (Figure 17) is an inhibitor of dihydroorotate dehydrogenase (DHODH) and is currently in clinical trials for PSC (NCT03722576). This drug is orally bioavailable and was identified as a potent FXR agonist (EC 50 = 450 nM) in a drug repositioning endeavor by Li et al 114 In an AlphaScreen assay, vidofludimus was found to be selective to FXR over closely related NRs.…”

Mechanistic Impact of Different Ligand Scaffolds on FXR Modulation Suggests Avenues to Selective Modulators

“…As outlined above, nuclear receptor activity depends on an equilibrium of co-repressor and co-activator binding, which is shifted upon ligand binding. , As a first step to elucidate FXR activation mechanisms, we probed the co-regulator binding effects of seven FXR agonists, providing a broad chemical and functional coverage of FXR activators, including the two most prominent steroidal FXR agonists CDCA and obeticholic acid (OCA), the three most prominent non-steroidal agonist scaffolds with GW4064, fexaramine, and WAY362450, as well as the partial agonist DM175, and the recently reported FXR ligand IMU-838 that showed very weak partial agonism (Figure a). Direct comparison of this set of FXR modulators in a uniform hybrid reporter gene assay revealed a broad spectrum of FXR activation efficacy (14–252% relative to the natural ligand CDCA, Table ), supporting its suitability to probe FXR activation mechanisms.…”

“…The lack of CSP in the tryptophan signal in the presence of IMU-838 and NCoR1 compared to the apo-state further indicates that helix H12 in the IMU-838-bound FXR LBD potentially adopts an inactive conformation and that a coactivator like NCoA is required to induce the active conformation observed in the co-crystal structure. 35 IMU-838 has Distinctive Effects on FXR Regulated Gene Expression. Mechanistic profiling by HTRF and NMR characterized IMU-838 as a new type of orthosteric FXR ligand that lacks the ability to recruit co-activators to the FXR LBD but on the other hand displaces the co-repressor NCoR1 with considerable potency (IC 50 = 0.34 μM).…”

Performance of Imaging Techniques in Non-invasive Diagnosis of Non-alcoholic Fatty Liver Disease in Children: A Systematic Review and Meta-Analysis

“…With the obesity epidemic ( 2 , 3 ), the prevalence of NAFLD in children has more than doubled in the last 20 years ( 4 ), and it has also become the most common chronic childhood liver disease worldwide ( 5 , 6 ). The prevalence of NAFLD in general children is 7.6%, while more than 34.2% in obese children ( 7 ).…”