Derivation of a retinoid X receptor scaffold from peroxisome proliferator-activated receptor gamma ligand 1-Di(1H-indol-3-yl)methyl-4-trifluoromethylbenzene.

1-Di(1H-indol-3-yl)methyl-4-trifluoromethyl benzene (DIM-Ph-4-CF3) is reported to inhibit cancer cell growth and to act as a transcriptional agonist of peroxisome proliferator-activated receptor gamma (PPAR gamma) and nuclear receptor 4A subfamily member 1 (NR4A1). In addition, DIM-Ph-4-CF3 exerts anticancer effects independent of these receptors because PPAR gamma antagonists do not block its inhibition of cell growth, and the small pocket in the NR4A1 crystal structure suggests no ligand can bind. Because PPAR gamma and NR4A1 heterodimerize with retinoid X receptor (RXR), and several PPAR gamma ligands transcriptionally activate RXR, DIM-Ph-4-CF3 was investigated as an RXR ligand. DIM-Ph-4-CF3 displaces 9-cis-retinoic acid from RXR alpha but does not transactivate RXR alpha. Structure-based design using DIM-Ph-4-CF3 as a template led to the RXR alpha transcriptional agonist (E)-3-[5-di(1-methyl-1H-indol-3-yl)methyl-2-thienyl]acrylic acid. Its docked pose in the RXR alpha ligand binding domain suggests that binding is stabilized by interactions of its carboxylate group with arginine 316, its indoles with cysteines 269 and 432, and its 1-methyl groups with hydrophobic residues lining the binding pocket. As is expected of a selective activator of RXR alpha, but not of RARs and PPAR gamma, this RXR alpha agonist, unlike DIM-Ph-4-CF3, does not appreciably decrease cancer cell growth or induce apoptosis at pharmacologically relevant concentrations.