The Benzenesulfoamide T0901317 [N-(2,2,2-Trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide] Is a Novel Retinoic Acid Receptor-Related Orphan Receptor-α/γ Inverse Agonist
The Benzenesulfoamide T0901317 [N-(2,2,2-Trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide] Is a Novel Retinoic Acid Receptor-Related Orphan Receptor-α/γ Inverse Agonist
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DOI：
10.1124/mol.109.060905
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发表时间：
2010-02-01
影响因子：
3.6
通讯作者：
Griffin, Patrick R.
中科院分区：
文献类型：
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作者：
Kumar, Naresh;Solt, Laura A.;Griffin, Patrick R.
视黄酸受体相关孤儿受体（ROR）调节多种生理过程，包括肝脏新生、脂质代谢、昼夜节律和免疫功能。在这里，我们提出了第一个高亲和力的ROR α和ROR γ的合成配体。在针对所有48种人核受体的筛选中，苯磺酰胺肝X受体（LXR）激动剂N-（2，2，2-三氟乙基）-N-[4-[2，2，2-三氟-1-羟基-1-（三氟甲基）乙基]苯基]-苯磺酰胺（T0901317）抑制ROR α和ROR γ的反式激活活性，但不抑制ROR β。发现T0901317以高亲和力（Ki分别为132和51 nM）直接结合ROR α和ROR γ，导致调节受体与转录辅因子蛋白相互作用的能力。T0901317抑制ROR应答报告基因的ROR α/γ依赖性反式激活，并在HepG 2细胞中减少内源性ROR靶基因（G6 β）处ROR α对类固醇受体共激活因子-2的募集。使用小的干扰RNA，我们证明，阻遏的hepG 2细胞中的致瘤酶葡萄糖-6-磷酸酶的T0901317是ROR依赖性的，并不是由于该化合物的LXR活性。总之，T0901317代表了一种新的化学探针，以检查ROR α/γ功能和ROR选择性调节剂的开发的一个很好的起点。更重要的是，我们的研究结果表明，小分子可用于靶向ROR，用于代谢和免疫疾病的治疗干预。
Retinoic acid receptor-related orphan receptors (RORs) regulate a variety of physiological processes including hepatic gluconeogenesis, lipid metabolism, circadian rhythm, and immune function. Here we present the first high-affinity synthetic ligand for both ROR alpha and ROR gamma. In a screen against all 48 human nuclear receptors, the benzenesulfonamide liver X receptor (LXR) agonist N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide (T0901317) inhibited transactivation activity of ROR alpha and ROR gamma but not ROR beta. T0901317 was found to directly bind to ROR alpha and ROR gamma with high affinity (K-i = 132 and 51 nM, respectively), resulting in the modulation of the receptor's ability to interact with transcriptional cofactor proteins. T0901317 repressed ROR alpha/gamma-dependent transactivation of ROR-responsive reporter genes and in HepG2 cells reduced recruitment of steroid receptor coactivator-2 by ROR alpha at an endogenous ROR target gene (G6Pase). Using small interference RNA, we demonstrate that repression of the gluconeogenic enzyme glucose-6-phosphatase in HepG2 cells by T0901317 is ROR-dependent and is not due to the compound's LXR activity. In summary, T0901317 represents a novel chemical probe to examine ROR alpha/gamma function and an excellent starting point for the development of ROR selective modulators. More importantly, our results demonstrate that small molecules can be used to target the RORs for therapeutic intervention in metabolic and immune disorders.