Natural products and synthetic analogs as selective orphan nuclear receptor 4A (NR4A) modulators

Although endogenous ligands for the orphan nuclear receptor 4A1 (NR4A1, Nur77), NR4A2 (Nurr1), and NR4A3 (Nor-1) have not been identified, several natural products and synthetic analogs bind NR4A members. These studies are becoming increasingly important since members of the NR4A subfamily of 3 receptors are potential drug targets for treating cancer and non-cancer endpoints and particularly those conditions associated with inflammatory diseases. Ligands that bind NR4A1, NR4A2, and NR4A3 including Cytosporone B, celastrol, bis-indole derived (CDIM) compounds, tryptophan/indolic, metabolites, prostaglandins, resveratrol, piperlongumine, fatty acids, flavonoids, alkaloids, peptides, and drug families including statins and antimalarial drugs. The structural diversity of NR4A ligands and their overlapping and unique effects on NR4A1, NR4A2, and NR4A3 suggest that NR4A ligands are selective NR4A modulators (SNR4AMs) that exhibit tissue-, structure-, and response-specific activities. The SNR4AM activities of NR4A ligands are exemplified among the Cytosporone B analogs where n-pentyl-2-[3,5-dihydroxy-2-(nonanoyl)]phenyl acetate (PDNPA) binds NR4A1, NR4A2 and NR4A3 but activates only NR4A1 and exhibits significant functional differences with other Cytosporone B analogs. The number of potential clinical applications of agents targeting NR4A is increasing and this should spur future development of SNR4AMs as therapeutics that act through NR4A1, NR4A2 and NR4A3.