PPARgamma agonist DIM-Ph-4-CF(3), a template for RXRalpha agonist (E)-3-[5-di(1-methyl-1H-indol-3-yl)methyl-2-thienyl]
acrylic acid: DIM-Ph-CF(3) is reported to inhibit
cancer growth independent of
PPARgamma and to interact with NR4A1. As both receptors dimerize with RXR, and natural
PPARgamma ligands activate RXR, DIM-Ph-4-CF(3) was investigated as an RXR
ligand. It displaces
9-cis-retinoic acid from RXRalpha but does not activate RXRalpha. Structure-based direct design led to an RXRalpha agonist.1-Di(1H-indol-3-yl)methyl-4-trifluoromethylbenzene (DIM-Ph-4-CF(3)) is reported to inhibit
cancer cell growth and to act as a transcriptional agonist of
peroxisome proliferator-activated receptor gamma (
PPARgamma) and
nuclear receptor 4A subfamily member 1 (NR4A1). In addition, DIM-Ph-4-CF(3) exerts anticancer effects independent of these receptors because
PPARgamma antagonists do not block its inhibition of cell growth, and the small pocket in the NR4A1 crystal structure suggests no
ligand can bind. Because
PPARgamma and NR4A1 heterodimerize with
retinoid X receptor (RXR), and several
PPARgamma ligands transcriptionally activate RXR, DIM-Ph-4-CF(3) was investigated as an RXR
ligand. DIM-Ph-4-CF(3) displaces
9-cis-retinoic acid from RXRalpha but does not transactivate RXRalpha. Structure-based design using DIM-Ph-4-CF(3) as a template led to the RXRalpha transcriptional agonist (E)-3-[5-di(1-methyl-1H-indol-3-yl)methyl-2-thienyl]
acrylic acid. Its docked pose in the RXRalpha
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 RXRalpha, but not of RARs and
PPARgamma, this RXRalpha agonist, unlike DIM-Ph-4-CF(3), does not appreciably decrease
cancer cell growth or induce apoptosis at pharmacologically relevant concentrations.