Derivation of a retinoid X receptor scaffold from peroxisome proliferator-activated receptor gamma ligand 1-Di(1H-indol-3-yl)methyl-4-trifluoromethylbenzene.
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.
Dawson
Marcia I
MI
Cancer Center, Burnham Institute for Medical Research, 10901 North Torrey Pines Rd., La Jolla, CA 92037, USA. mdawson@burnham.org
Ye
Mao
M
Cao
Xihua
X
Farhana
Lulu
L
Hu
Qiong-Ying
QY
Zhao
Yong
Y
Xu
Li Ping
LP
Kiselyuk
Alice
A
Correa
Ricardo G
RG
Yang
Li
L
Hou
Tingjun
T
Reed
John C
JC
Itkin-Ansari
Pamela
P
Levine
Fred
F
Sanner
Michel F
MF
Fontana
Joseph A
JA
Zhang
Xiao-Kun
XK
D001665:Binding Sites; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D003198:Computer Simulation; D004268:DNA-Binding Proteins / Q000378:metabolism; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005464:Fluorobenzenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism; D047488:Retinoid X Receptors / Q000819:agonists / Q000378:metabolism*
D004268:DNA-Binding Proteins; D005464:Fluorobenzenes; D008024:Ligands; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D047495:PPAR gamma; D011987:Receptors, Steroid; D047488:Retinoid X Receptors