Activity Screening of Fatty Acid Mimetic Drugs Identified Nuclear Receptor Agonists

Abstract

Fatty acid mimetics (FAM) are bioactive molecules acting through the binding sites of endogenous fatty acid metabolites on enzymes, transporters, and receptors. Due to the special characteristics of these binding sites, FAMs share common chemical features. Pharmacological modulation of fatty acid signaling has therapeutic potential in multiple pathologies, and several FAMs have been developed as drugs. We aimed to elucidate the promiscuity of FAM drugs on lipid-activated transcription factors and tested 64 approved compounds for activation of RAR, PPARs, VDR, LXR, FXR, and RXR. The activity screening revealed nuclear receptor agonism of several FAM drugs and considerable promiscuity of NSAIDs, while other compound classes evolved as selective. These screening results were not anticipated by three well-established target prediction tools, suggesting that FAMs are underrepresented in bioactivity data for model development. The screening dataset may therefore valuably contribute to such tools. Oxaprozin (RXR), tianeptine (PPARδ), mycophenolic acid (RAR), and bortezomib (RAR) exhibited selective agonism on one nuclear receptor and emerged as attractive leads for the selective optimization of side activities. Additionally, their nuclear receptor agonism may contribute relevant and valuable polypharmacology.