Fragment-based discovery of dual ligand pharmacophores for lipid-sensing transcription factors for designed polypharmacology

Designed polypharmacology aims to exploit additive or synergistic effects of simultaneous multi-target modulation. Multifactorial diseases like metabolic dysfunction requiring multi-drug treatment may significantly benefit from this concept. To identify multi-target lead pharmacophores for the development of designed dual ligands, we performed a focused two-stage screening of fatty acid mimetic fragments for modulation of the nuclear receptors THR, PPAR, FXR and RXR which are involved in transcriptional regulation of metabolic balance. Dual, multiple and pan-agonist hits were retrieved for various combinations of these targets of interest and preliminary SAR evaluation yielded dual agonist and pan-agonist fragments with attractive potency and efficacy as valuable leads for polypharmacology.