Orphan Nuclear Receptor 4A1 (NR4A1) and NR4A2 as Drug Targets
No Thumbnail Available
Date
2023-08-04
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
NR4A subfamily is a group of orphan nuclear receptors with no known endogenous ligands and includes three members: NR4A1, NR4A2, and NR4A3. NR4A members play important roles in maintaining cellular hemostasis and are involved in multiple diseases. NR4A1 is overexpressed in many inflammatory diseases including solid tumors and is involved in regulation of immune functions. Although an endogenous ligand for NR4A1 has not been identified, several different classes of compounds bind NR4A1 and these include cytosporone B and structurally related analogs, the triterpenoid celastrol and several polyunsaturated fatty acids. Our laboratory has characterized bis-indole derived (CDIM) compounds and multiple polyphenolics as NR4A1 ligands and these compounds are being investigated as novel mechanism-based anticancer agents. This study will take advantage of phytochemical-derived and newly discovered CDIMs compounds that exhibit direct binding to the ligand binding domain of NR4A1 and investigate their role as NR4A1 antagonists (or inverse NR4A1 agonists) that block tumor growth. This study identified natural products such as resveratrol, piperlongumine, quercetin, and kaempferol as NR4A1 ligands with effects similar to that observed for inverse N4AR1 agonists. These natural products show potential as therapeutic strategies for NR4A1-associated diseases. The study found that resveratrol binds NR4A1 with high affinity and acts as an antagonist that inhibits NR4A1- dependent transactivation in lung cancer cells, suggesting that its anticancer activity may be mediated through inhibition of NR4A1. Furthermore, resveratrol acts like an inverse NR4A1 agonist and modulates NR4A1-dependent genes and pathways, suggesting its potential as a selective receptor modulator. Piperlongumine has also been shown to inactivate NR4A1, thereby enhancing its anticancer activity. Furthermore, flavonoids including quercetin and kaempferol have been shown to suppress endometriosis by modulating NR4A1-mediated pathways. progress. Due to their natural origin, these natural products have the potential to be safe and tolerable therapeutic candidates. Furthermore, CDIM-derived compounds have been identified as novel dual NR4A1/NR4A2 ligands that are expected to inhibit cancer-promoting pathways and provide new avenues for disease therapy. This study will promote the development and application of natural and synthetic NR4A1/2 inverse agonists as precision therapeutics for targeting cancer and endometriosis patients who have high levels of NR4A1/2 expression.
Description
Keywords
NR4A1, NR4A2, Drug Development, Cancer, Resveratrol, Piperlongumine, Quercetin, Kaempferol