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.

Structural Optimization of Oxaprozin for Selective Inverse Nurr1 Agonism

“…The solvent from the combined organic layers was evaporated under reduced pressure to obtain 43 as a colorless solid (0.14 g, 97%). 1 (44). Methyl 2-{[(4,5-diphenyl-1,3-oxazol-2-yl)methyl](methyl)amino}propanoate (86, 0.10 g, 0.29 mmol, 1.0 equiv) was suspended in aqueous KOH solution (2 mL, 20%) and stirred at 50 °C for 20 h. After cooling to rt, pH was adjusted to 3−4 with aqueous HCl solution (10%).…”

“…Generating selectivity over RXR was a key objective of this study and achieved with the inverse Nurr1 agonists 30 , 36 , 53 and 55 . However, the typical fatty acid mimetic structure of oxaprozin and derivatives suggests potential interaction also with other related receptors , and we hence profiled the activity of the optimized compounds on fatty acid and lipid-sensing nuclear receptors (Figure b). 30 , 36 , 53 and 55 were in general favorably selective.…”

Genome analysis reveals hepatic transcriptional reprogramming changes mediated by enhancers during chick embryonic development

“…Many reports support the notion that HNF4A is a master regulator of hepatocyte phenotype and can regulate gene expression by binding promoter regions and coordinating lipolysis, p53, and bile acid signaling pathways, thereby preventing diet-induced NAFLD development ( Xu et al, 2021 ; Yang et al, 2021b ). RXR, ERRA and FOXA2 were reported to develop functions in lipid metabolism, endocrine, and immune system, respectively ( Wahab et al, 2019 ; Helmstädter et al, 2022 ; Yánez et al, 2022 ). Taken together, these screened TFs might be involved in the regulation of organ development and lipid metabolism during embryonic periods.…”