Development of fatty acid mimetic fragments as agonist tools for lipid-sensing transcription factors

Fatty acid mimetics (FAMs) are bioactive molecules with attractive drug-like chemical features. They are acting through the binding sites of endogenous fatty acid metabolites on enzymes, transporters and receptors. Therefore, FAMs might offer new opportunities in ligand development for lipid-sensing transcription factors.     
Nuclear receptors (NRs) are a family of ligand-activated transcription factors that regulate several physiological processes. The three NR4A receptors Nur77, Nurr1 and NOR-1 holding promising therapeutic potential in neurodegenerative diseases. Binding of prostaglandin E1 and its dehydrated metabolite (PGA1) suggested that NR4A receptors interact with FAMs. The liver receptor homolog-1 (LRH-1) is an orphan member of the NR family with therapeutic potential in metabolic diseases and hepatic inflammation. Recent studies identified LRH-1 as a cellular phospholipid sensor. Designed polypharmacology has emerged as an innovative strategy for the development of small molecules that achieve an improved therapeutic effect by simultaneously influencing two or more target molecules. NRs THR, PPARγ and FXR are fatty acid and lipid-sensing transcription factors and regulate metabolic balance in different tissues. Moreover, PPARγ and FXR are heterodimer partner of RXR. Synergies may also be accessible by simultaneous activation of both heterodimer partners. 
To explore FAMs as putative NR-ligands we have established a custom focused library of 92 chemically diverse fragment-like FAMs and screened it for the modulation of THR, PPARγ, FXR, RXR and LRH-1, as well as the three NR4A receptors.         
The activity screening revealed NR agonism of several FAM fragments. We identified benzyloxy benzoic acid derivatives as potent NR4A modulators with nanomolar-potencies. New LRH-1 ligand chemotypes for further optimization have been developed and moreover, we established dual modulator fragments for THR/PPARγ which involve in transcriptional regulation of metabolic balance. Overall, our screening results and preliminary structure-activity-relationship studies offer great potential of FAMs to obtain potent modulators for lipid-sensing transcription factors.