A Commentary on Dual Orphan Nuclear Receptor 4A1 (NR4A1) and NR4A2 Ligands

1,1-Bis(3'-indolyl)-1-(3,5-disubstitutedphenyl)methane (DIM-3,5) compounds in the presence or absence of a 4-hydroxylphenyl group bind both orphan nuclear receptor 4A1 (NR4A1) and NR4A2. In cancer cells, these compounds bind and inactivate pro-oncogenic NR4A1 and NR4A2 and downstream pathways acting as inverse agonists that inhibit cancer cell growth, survival, migration and invasion, and induce ferroptosis. Similar results are observed in endometriotic cells where the DIM-3,5 dual NR4A1/2 ligands inhibit NR4A1/NR4A2-mediated pro-endometriotic genes and pathways. The potency of these DIM-3,5 dual NR4A1/NR4A2 ligands is also observed in tumor infiltrating lymphocytes where both receptors are expressed and regulate comparable functions.