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

Abstract

Abstract1-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 γ (PPARγ) and nuclear receptor 4A subfamily member 1 (NR4A1). In addition, DIMPh-4-CF 3 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-CF 3 was investigated as an RXR ligand. DIM-Ph-4-CF 3 displaces 9-cis-retinoic acid from RXRα but does not transactivate RXRα. Structure-based design using DIM-Ph-4-CF 3 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-CF 3 , does not appreciably decrease cancer cell growth or induce apoptosis at pharmacologically relevant concentrations.

Nuclear Receptor Nur77 Deficiency Alters Dendritic Cell Function

“…They have been shown to regulate Nur77 function by modulating Nur77-dependent transactivation, influencing its expression levels, inducing nuclear export of Nur77 or affecting binding to other proteins ( 80 – 88 ). Many of these compounds have, as also shown for 6-MP, also Nur77-independent actions ( 85 , 89 , 90 ). In cancer cells, neuronal cells, as well as different immune cells, it has been shown that Nur77 function depends on tissue context, subcellular localization, external stimuli, protein–protein interactions, or post-translational modifications ( 22 – 26 , 31 , 32 , 34 , 35 , 37 , 38 , 60 ).…”

Structure–Activity Relationship and Pharmacokinetic Studies of Sotrastaurin (AEB071), a Promising Novel Medicine for Prevention of Graft Rejection and Treatment of Psoriasis

“…29 was synthesized as described for 1 , but the final cyclocondensation was conducted with (1-isopropyl-1 H -indol-3-yl)oxoacetic acid methyl ester, which was synthesized from 1-isopropyl-1 H -indole as described . ES-MS: 481 [M + H] + .…”

“…25 Hz, 1H), 8.12 (s, 1H), 11.2À11.4 (br, 1H), 11.9À12.2 (br, 1H). 13 3-(7-Chloro-1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]pyrrole-2,5-dione (26). 26 was synthesized as described for 1, but the final cyclocondensation was conducted with commercially available (7- 3-(1-Isopropyl-1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]pyrrole-2,5-dione (29).…”

A Unique Pharmacophore for Activation of the Nuclear Orphan Receptor Nur77 In vivo and In vitro

“…The synthetic Nur77 agonists 1,1-di(3-indolyl)-1-(p-substituted-phenyl)methanes (DIM-arenes) have been shown to affect Nur77 activation in a structure-dependent manner. Interestingly, DIM-arenes also act as transcriptional agonists for PPARγ and RXRα (22), suggesting that they are not specific agonists for Nur77. We recently found that the natural product cytosporone B (Csn-B), an Nur77 agonist isolated from Dothiorella sp.…”