生物活性

T0070907 is a cell-permeable chloro-nitro-benzamido compound that acts as a potent, specific, irreversible, and high-affinity antagonist of PPARγ with a Ki of 1 nM. Displays >800-fold greater selectivity for PPARg over PPARa and PPARd (Ki = 0.85 μM and 1.8 μM, respectively). Blocks hormone- and agonist-induced adipogenesis in 3T3-L1 cells. It suppresses interactions between PPARg and coactivator-derived peptides, while promotes the recruitment of corepressor-derived peptides. Shown to modulate the interaction of PPARg2 with the cofactor proteins through covalent binding to Cys313 in its ligand-binding domain.

T0070907selective inhibits PPARγ antagonist with IC50 of 1 nM.[1]

Bindingaffinity of T0070907 to the PPARs[1] 

体外研究

体内研究

1% DMSO+30% polyethylene glycol+1% Tween 80

激酶实验

Ligand Binding Assay[1]

To determine the binding affinity of T0070907to the PPARs, scintillation proximity assay (SPA) was performed with thefollowing modifications. A 90-μl reaction contained SPA buffer (10 mM K2HPO4,10 mM KH2PO4, 2 mM EDTA, 50 mM NaCl, 1 mM dithiothreitol,2 mM CHAPS, 10% (v/v) glycerol, pH 7.1), 50 ng of GST-PPARγ(or 150 ng of GST-PPARα, GST-PPARδ), 5 nM3H-labeled radioligands, and 5μlof T0070907 in Me2SO. After incubation for 1 h at room temperature,10μl of polylysine-coated SPA beads (at 20 mg/ml in SPA buffer) wereadded, and the mixture was incubated for 1 h before reading in PackardTopcount. [3H]Rosiglitazone was used for PPARγ,and [3H]GW2433 was used for PPARαand PPARδ.

细胞实验

CellCulture and Treatments[2]

HeLa (HPV 18), SiHa (HPV 16), and ME-180(HPV 68) cells with wild-type p53 were cultured in Dulbecco Modified Eagle Mediumwith 100 units/mL penicillin, 100μg/mL streptomycin, and 10% fetalbovine serum (FBS) and incubated at 37oC in a humidified atmosphereof 95% air and 5% CO2. T0070907 was dissolved in dimethyl sulfoxide(DMSO) vehicle. Cells were treated with 50μmol/L atindicated time points with 0.1% FBS media and then cells were irradiated with a6 MV linear accelerator, at a dose rate of 3 Gy/min and incubated at 37oCat indicated time points.

ClonogenicAssay

Cells in growing phase were treated witheither vehicle (DMSO) or T0070907 50 mmol/L at indicated time points and thenirradiated. Varying number (100-2000) of cells for optimal colony counting wasseeded in 60-mm dishes according to the presence or absence of T0070907 andradiation. After 14 days, the cells were stained with 0.1% crystal violetsolution and colonies which are composed of at least 50 cells were counted.

动物实验

In vivo metastasis study[3]

Five-week-old male SCID mice were maintainedin a specific pathogen-free environment. Six-week-old mice were used in thisexperiment. To assay metastatic capability, viable cancer cells were suspendedin serum-free medium, and 20-μL aliquots of cell suspension containing 2 × 106cells were inoculated into the spleens of SCID mice under anesthesia. Afterinoculation, the mice were randomized into two treatment groups (n = 6) and onecontrol group (n = 6). Administration of T0070907 (5 mg/kg/day) to eachtreatment group began 1 day after cell inoculation and continued daily for 4weeks. Four weeks after inoculation, the mice were killed and autopsiedimmediately. Liver metastasis was measured by counting macroscopic lesions, andmeasuring them to calculate tumor volume: length/2 × width/2 × height/2 × 4/3 ×π. Examination of hematoxylin–eosin-stained sections of each lesion resulted inassessments of histopathological alterations in liver metastases.

不同实验动物依据体表面积的等效剂量转换表（数据来源于FDA指南）

例如，已知某工具药用于小鼠的剂量为88 mg/kg , 则用于大鼠的剂量换算方法：将88 mg/kg 乘以小鼠的Km系数（3），再除以大鼠的Km系数（6），得到该药物用于大鼠的等效剂量44 mg/kg。

参考文献

[1] Lee G, Elwood F, McNally J, et al. T0070907, a selective ligand for peroxisome proliferator-activated receptor gamma, functions as an antagonist of biochemical and cellular activities. J Biol Chem. 2002;277(22):19649-19657.
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体内溶解度
约28 mg/mL

Clinical Trial Information ( data from http://clinicaltrials.gov )

注：以上所有数据均来自公开文献，并不保证对所有实验均有效，数据仅供参考。

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