The Farnesoid X Receptor (FXR)
Ongoing research projects (FXR)
The Farnesoid X Receptor (FXR) is a nuclear receptor that acts as a ligand activated transcription factor and is responsible for the regulation of expression of several genes, which play a central role within glucose and lipid homeostasis. Here, especially modulation of the expression of the small heterodimer partner (SHP) or the sterol regulatory element binding protein 1c (SREBP-1c) plays an important role. SHP and SREBP-1c themselves act as transcription factors and influence on prodedures like gluconeogenesis, glycogen synthesis and fatty acid synthesis and degradation. In animal models, FXR activation leads to an improved insulin senisitivity, decreased blood glucose levels and beneficial effects on triglyceride levels in blood. FXR knockout animals show several disturbances within glucose metabolism and lipid homeostasis.
In the last decade, FXR has emerged as an attractive target for drug development for the treatment of diabetes mellitus, dyslipidemia and hepatic disorders like NASH (Non-alcoholic steatohepatitis) in pharmaceutical industry as well as in academia. Much effort has been made to develop new lead structures and some have already been characterized in animal models or in early clinical studies in healthy humans. But until now there is no candidate which has reached later phases of clinical development and promising compounds like GW4064 have not been further developd due to pharmakokinetic or toxicological issues. The need to find new lead structures to follow the promising way of modulating FXR for treatment of several diseases is obvious.
A part of our working group deals with the development and synthesis of FXR modulators and their structure-activity relationships. Therefore, established methods of organic synthesis are used, supported by computational methods like virtual screening and molecular docking. Potentially active compounds first are identified in silico and then synthesized by organic synthesis methods. In the last years, there were several in vitro repotergene assays established in the working group to characterize the synthesized compounds concerning their ability to activate FXR.
- Steri R., Kara M., Proschak E., Schubert-Zsilavecz M.
Antidiabetic sulfonylureas modulate Farnesoid X Receptor activation and target gene transcription
Future Medicinal Chemistry 2010; 2 (4): 575-586
- Steri R., Schneider P., Klenner A., Rupp M., Schubert-Zsilavecz M., Schneider G.
Target profile prediction: Cross-activation of Peroxisome proliferator-activated Receptor (PPAR) and Farnesoid X Receptor (FXR)
Molecular Informatics 2010; 4: 287-292