Derivation of a Retinoid X Receptor Scaffold from Peroxisome Proliferator‐Activated Receptor γ Ligand 1‐Di(1H‐indol‐3‐yl)methyl‐4‐trifluoromethylbenzene

Abstract

PPARγ agonist DIM‐Ph‐4‐CF₃, a template for RXRα agonist (E)‐3‐[5‐di(1‐methyl‐1H‐indol‐3‐yl)methyl‐2‐thienyl] acrylic acid: DIM‐Ph‐CF₃ is reported to inhibit cancer growth independent of PPARγ and to interact with NR4A1. As both receptors dimerize with RXR, and natural PPARγ ligands activate RXR, DIM‐Ph‐4‐CF₃ was investigated as an RXR ligand. It displaces 9‐cis‐retinoic acid from RXRα but does not activate RXRα. Structure‐based direct design led to an RXRα agonist. 1‐Di(1H‐indol‐3‐yl)methyl‐4‐trifluoromethylbenzene (DIM‐Ph‐4‐CF₃) is reported to inhibit cancer cell growth and to act as a transcriptional agonist of peroxisome proliferator‐activated receptor γ (PPARγ) and nuclear receptor 4A subfamily member 1 (NR4A1). In addition, DIM‐Ph‐4‐CF₃ exerts anticancer effects independent of these receptors because PPARγ antagonists do not block its inhibition of cell growth, and the small pocket in the NR4A1 crystal structure suggests no ligand can bind. Because PPARγ and NR4A1 heterodimerize with retinoid X receptor (RXR), and several PPARγ ligands transcriptionally activate RXR, DIM‐Ph‐4‐CF₃ was investigated as an RXR ligand. DIM‐Ph‐4‐CF₃ displaces 9‐cis‐retinoic acid from RXRα but does not transactivate RXRα. Structure‐based design using DIM‐Ph‐4‐CF₃ as a template led to the RXRα transcriptional agonist (E)‐3‐[5‐di(1‐methyl‐1H‐indol‐3‐yl)methyl‐2‐thienyl]acrylic acid. Its docked pose in the RXRα 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 RXRα, but not of RARs and PPARγ, this RXRα agonist, unlike DIM‐Ph‐4‐CF₃, does not appreciably decrease cancer cell growth or induce apoptosis at pharmacologically relevant concentrations.