Derivation of a retinoid X receptor scaffold from peroxisome proliferator-activated receptor gamma ligand 1-Di(1H-indol-3-yl)methyl-4-trifluoromethylbenzene.
Derivation of a retinoid X receptor scaffold from peroxisome proliferator-activated receptor gamma ligand 1-Di(1H-indol-3-yl)methyl-4-trifluoromethylbenzene.
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DOI：
10.1002/cmdc.200800447
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发表时间：
2009-07
期刊：
影响因子：
3.4
通讯作者：
Zhang, Xiao-Kun
中科院分区：
文献类型：
--
作者：
Dawson, Marcia I.;Ye, Mao;Cao, Xihua;Farhana, Lulu;Hu, Qiong-Ying;Zhao, Yong;Xu, Li Ping;Kiselyuk, Alice;Correa, Ricardo G.;Yang, Li;Hou, Tingjun;Reed, John C.;Itkin-Ansari, Pamela;Levine, Fred;Sanner, Michel F.;Fontana, Joseph A.;Zhang, Xiao-Kun
1-二（1H-吲哚-3-基）甲基-4-三氟甲基苯（DIM-Ph-4-CF 3）被报道抑制癌细胞生长，并作为过氧化物酶体增殖物激活受体γ（PPARγ）和核受体4A亚家族成员1（NR 4A 1）的转录激动剂。此外，DIM-Ph-4-CF 3发挥的抗癌作用不依赖于这些受体，因为PPARγ拮抗剂不能阻断其对细胞生长的抑制，并且NR 4A 1晶体结构中的小口袋表明没有配体可以结合。由于PPARγ和NR 4A 1与类视黄醇X受体（RXR）异源二聚化，并且几种PPARγ配体转录激活RXR，因此研究了DIM-Ph-4-CF 3作为RXR配体。DIM-Ph-4-CF 3从RXRα置换9-顺式-视黄酸，但不反式激活RXRα。使用DIM-Ph-4-CF 3作为模板进行基于结构的设计，得到了RXRα转录激动剂（E）-3-[5-二（1-甲基-1H-吲哚-3-基）甲基-2-噻吩基]丙烯酸。其在RXRα配体结合结构域中的对接姿势表明，结合通过其羧酸基团与精氨酸316、其吲哚与半胱氨酸269和432以及其1-甲基与衬在结合口袋中的疏水残基的相互作用而稳定。与预期的RXRα选择性激活剂（而不是RAR和PPARγ）一样，与DIM-Ph-4-CF 3不同，该RXRα激动剂在药物相关浓度下不会明显降低癌细胞生长或诱导凋亡。
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.
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