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Derivation of a Retinoid X Receptor Scaffold from Peroxisome Proliferator‐Activated Receptor γ Ligand 1‐Di(1 H ‐indol‐3‐yl)methyl‐4‐trifluoromethylbenzene
Author(s) -
Dawson Marcia I.,
Ye Mao,
Cao Xihua,
Farhana Lulu,
Hu QiongYing,
Zhao Yong,
Xu Li Ping,
Kiselyuk Alice,
Correa Ricardo G.,
Yang Li,
Hou Tingjun,
Reed John C.,
ItkinAnsari Pamela,
Levine Fred,
Sanner Michel F.,
Fontana Joseph A.,
Zhang XiaoKun
Publication year - 2009
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200800447
Subject(s) - retinoid x receptor , peroxisome proliferator activated receptor , agonist , nuclear receptor , retinoid x receptor alpha , receptor , chemistry , ligand (biochemistry) , retinoic acid , retinoic acid receptor , biology , biochemistry , transcription factor , gene
PPARγ agonist DIM‐Ph‐4‐CF 3 , a template for RXRα agonist ( E )‐3‐[5‐di(1‐methyl‐1 H ‐indol‐3‐yl)methyl‐2‐thienyl] acrylic acid: DIM‐Ph‐CF 3 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‐CF 3 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(1 H ‐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, DIM‐Ph‐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‐1 H ‐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.