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
Cancer Center, Burnham Institute for Medical Research, 10901 North Torrey Pines Rd., La Jolla, CA 92037, USA.
ChemMedChem. 2009 Jul;4(7):1106-19. doi: 10.1002/cmdc.200800447.
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.
过氧化物酶体增殖物激活受体γ（PPARγ）激动剂DIM-Ph-4-CF(3)，一种视黄醇X受体α（RXRα）激动剂（E）-3-[5-二（1-甲基-1H-吲哚-3-基）甲基-2-噻吩基]丙烯酸的模板：据报道，DIM-Ph-CF(3)可独立于PPARγ抑制癌症生长，并与核受体4A亚家族成员1（NR4A1）相互作用。由于这两种受体均与RXR形成二聚体，且天然PPARγ配体可激活RXR，因此对DIM-Ph-4-CF(3)作为RXR配体进行了研究。它可从RXRα上置换9-顺式视黄酸，但不能激活RXRα。基于结构的直接设计得到了一种RXRα激动剂。据报道，1-二（1H-吲哚-3-基）甲基-4-三氟甲基苯（DIM-Ph-4-CF(3)）可抑制癌细胞生长，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（NR4A1）的转录激动剂。此外，DIM-Ph-4-CF(3)发挥抗癌作用与这些受体无关，因为PPARγ拮抗剂不能阻断其对细胞生长的抑制作用，且NR4A1晶体结构中的小口袋表明没有配体可以结合。由于PPARγ和NR4A1与视黄醇X受体（RXR）形成异源二聚体，且几种PPARγ配体可转录激活RXR，因此对DIM-Ph-4-CF(3)作为RXR配体进行了研究。DIM-Ph-4-CF(3)可从RXRα上置换9-顺式视黄酸，但不能反式激活RXRα。以DIM-Ph-4-CF(3)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配体结合域中的对接构象表明，其羧基与精氨酸316的相互作用、吲哚与半胱氨酸269和432的相互作用以及1-甲基与结合口袋内衬疏水残基的相互作用稳定了结合。正如RXRα选择性激活剂所预期的那样，但不是维甲酸受体（RAR）和PPARγ的选择性激活剂，与DIM-Ph-4-CF(3)不同，这种RXRα激动剂在药理学相关浓度下不会明显降低癌细胞生长或诱导细胞凋亡。
