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T0901317

现货
Catalog No.
A2249
肝X受体激动剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 600.00
现货
25mg
¥ 600.00
现货
100mg
¥ 1,700.00
现货

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Background

T0901317 is an agonist for multiple targets, which possesses EC50 values of 20 nM and 5 μM for LXRα and FXR, respectively. Furthermore, it is RORα and RORγ dual inverse agonist with estimated IC50 of 2.0 μM and 1.7 μM, respectively. [1, 2]

LXRs play central roles in cholesterol metabolism, which are nuclear receptors that regulate the metabolism of several important lipids, including cholesterol and bile acids. LXRs were first identified as orphan members of the nuclear receptor superfamily. Like LXRs, FXR was also initially thought as an orphan member of the nuclear receptor superfamily. But FXR was later identified as the physiological receptor for bile acids and shown to regulate a feedback loop for bile acid transport and synthesis as well as modulating additional functions in lipid metabolism. Retinoic acid receptor-related orphan receptors (RORs) are important in a variety of physiological processes including hepatic gluconeogenesis, lipid metabolism, circadian rhythm, and immunological functions. T0901317 inhibited transactivation activity of RORα and RORγ by direct binding with high affinity which led to the regulation of the receptor’s ability to interact with transcriptional cofactor proteins, but did not show inhibitory activity against RORβ. [1, 2]

A short synthetic rhodamine-labeled peptide was used to conduct a fluorescence polarization assay for T0901317 binding to LXRα. In this homogeneous biochemical assay, the greater the extent of rhodamine-peptide binding to LXR, the greater the extent of fluorescence polarization observed. The potency of T0901317 binding to LXRα was determined, which possessed EC50 of 20 nM. Adopting HEK293 cells transfected with Gal4 DBD-FXR ligand-binding-domain chimeric receptor along with Gal4-responsive luciferase reporter, T0901317 activated FXR with an EC50 of ~5 uM, which surpassed the potency of natural FXR ligand. Moreover, using a cell-based GAL4-NR LBD cotransfection assay, it was found that T0901317 at a dose of 2 μM was a potent in repressing both GAL4-RORα and GAL4-RORγ. Furthermore, T0901317 was demonstrated its selectivity that T0901317 inhibited the constitutive transactivation activity of both GAL4-RORα and GAL4-RORγ with little or no activity on GAL4-RORβ T0901317 demonstrated an excellent dose response, with an estimated IC50 values of 2.0 for RORα and 1.7 μM for RORγ, respectively. [1, 2, 3]

The role of T0901317 on ABCA1 expression in vivo was also studied. We treated 11-week-old APP23 mice orally by gastric gavage for 6 days with 50 mg/kg/day T0901317. The treatment of APP23 mice resulted in a substantial increase in the expression of ABCA1, however the expression of APP did not change. [4]

References:
[1].  Schultz J R, Tu H, Luk A, et al. Role of LXRs in control of lipogenesis[J]. Genes & development, 2000, 14(22): 2831-2838.
[2].  Kumar N, Solt L A, Conkright J J, et al. 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[J]. Molecular pharmacology, 2010, 77(2): 228-236.
[3].  Houck K A, Borchert K M, Hepler C D, et al. T0901317 is a dual LXR/FXR agonist[J]. Molecular genetics and metabolism, 2004, 83(1): 184-187.
[4].  Liu Y, Yan C, Wang Y, et al. Liver X receptor agonist T0901317 inhibition of glucocorticoid receptor expression in hepatocytes may contribute to the amelioration of diabetic syndrome in db/db mice[J]. Endocrinology, 2006, 147(11): 5061-5068.

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt481.33
Cas No.293754-55-9
FormulaC17H12F9NO3S
Solubility≥24.05mg/mL in DMSO
Chemical NameN-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-N-(2,2,2-trifluoroethyl)benzenesulfonamide
SDFDownload SDF
Canonical SMILESC1=CC=C(C=C1)S(=O)(=O)N(CC(F)(F)F)C2=CC=C(C=C2)C(C(F)(F)F)(C(F)(F)F)O
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

激酶实验[1]:

结合实验

将LXR配体结合结构域与谷胱甘肽S-转移酶(GST)的C末端融合,并将所得的GST-LXR蛋白在大肠杆菌中表达并于谷胱甘肽珠上纯化。将10 nM罗丹明标记的肽(ILRKLLQE)在振荡器上与400 nM GST-LXR和T0901317溶于100 μL缓冲液(10 mMHepes、150 mMNaCl、2mM MgCl2、5mM DTT、pH7.9)的96孔板中,在LJL分析器(LJL Biosystems)上测量荧光偏振(mP)。

细胞实验 [1]:

细胞系

转染表达人LXRα质粒的HEK293细胞。

溶解方法

该化合物在DMSO中的溶解度大于10 mM。若配制更高浓度的溶液,一般步骤如下:请将试管置于37℃加热10分钟和/或将其置于超声波浴中震荡一段时间。原液于-20℃可放置数月

反应条件

20 h.

实验结果

T0901317是一种高效和选择性非甾体类的LXR配体。T0901317诱导接近8倍的LXRα的转录活性,EC50值为20 nM。T0901317还反式激活嵌合体Gal4-LXRα和Gal4-PXR(孕烷X受体)。

动物实验 [1]:

动物模型

6至10周龄C57BL/6小鼠; 12至16周龄的金色叙利亚仓鼠。

剂量

小鼠: 5、50 mg/kg,口服;仓鼠: 3、10、30 mg/kg,口服.

实验结果

口服T0901317的C57BL/6小鼠血浆中甘油三酯的水平显著增加。在仓鼠中,T0901317也增加血浆甘油三酯。此外,T0901317增加脂肪酸代谢相关基因和肝脂肪酸生物合成基因(ACC (2倍), FAS (3倍)和SCD-1 (9倍))的表达。

注意事项

请测试所有化合物在室内的溶解度,实际溶解度和理论值可能略有不同。这是由实验系统的误差引起的,属于正常现象。

References:

[1]. Schultz JR, Tu H, Luk A, et al. Role of LXRs in control of lipogenesis. Genes Dev, 2000, 14(22): 2831-2838.

生物活性

描述 T0901317是一种有效的和选择性的LXRα和LXRβ激动剂,Kd值分别为7 nM和22 nM。
靶点 LXRα LXRβ        
IC50 7 nM 22 nM        

质量控制

化学结构

T0901317