| 名称 | SB 525334 |
| 描述 | SB-525334 is a potent and selective inhibitor of the TGF-β1R and ALK5 (IC50: 14.3 nM). |
| 细胞实验 | RPTE cells were seeded on microscope slides. The following day, the cells were starved by removal of epidermal growth factor and serum for 24 h prior to dosing. Cells were dosed with 10 ng/ml TGF- 1 or 1 M SB-525334 or a combination of both. Slides were pretreated with SB-525334 or starve media for 3 h prior to a 1-h incubation at 37°C with TGF- 1 or starve media. The cells were then fixed for 15 min in 4% ice-cold paraformaldehyde. The cells were permeabilized for 10 min in 0.3% Triton X-100/PBS at room temperature. The slides were incubated for 30 min in a blocking solution containing 0.3% bovine serum albumin, 10% FBS, 0.3% Triton X-100/PBS, and 5% milk in PBS. A 1:200 dilution of primary mouse anti-Smad2/3 antibody was applied to each slide for overnight incubation. A 1:200 dilution of anti-mouse IgG fluorescein secondary antibody was applied to each slide for 30 min at room temperature. The slides were then viewed using an argon blue 488 nM laser in a confocal microscope. Nuclear signal intensity was analyzed using 1D Image Analysis software. The relative intensity was determined by the mean intensity of the nucleus and expressed as percent control [1]. |
| 激酶实验 | To determine the potency of the ALK5 inhibitor SB-525334 at the enzyme level, purified GST-tagged kinase domain of ALK5 was incubated with purified GST-tagged full-length Smad3 in the presence of 33P-γATP and different concentrations of SB525334. The readout is radioactively labeled Smad3. To determine the selectivity of SB-525334, purified GST-tagged kinase domain of ALK2 and ALK4 were incubated with GST-tagged full-length Smad1 and Smad3, respectively, in the presence of different concentrations of SB-525334 (n=3). IC50 value determinations were calculated with GraphPad software using a sigmoidal dose-response curve [1]. |
| 动物实验 | To identify the optimal treatment length for puromycin aminonucleoside's effect on extracellular matrix in the kidney, 18 Sprague-Dawley (SD) rats (200 –250 g) were injected with 15 mg/100 g of puromycin aminonucleoside in 0.9% saline or sham 0.9% saline only intraperitoneally. Animals were sacrificed at 24 h (n = 3+2 control), day 4 (n=3), day 8 (n = 3), day 10 (n = 3), day 15 (n = 2), and day 20 (n = 2). A 24-h urine collection and plasma sample were taken at 9:00 AM everyday. Urine and plasma chemistry were measured at GlaxoSmithKline Laboratories Animal Science using an Olympus clinical analyzer. Proteinuria was measured as a concentration (mg/deciliter) and then converted to total protein excreted over a 24-h period using urine flow (mL/24 h). The creatinine clearance was calculated by multiplying urine creatinine levels (mg/mL) by urine flow (mg/mL/100 g b.wt.) and then dividing that product by plasma creatinine (mg/mL). To determine the effect of SB-525334 on renal disease in the PAN model, SD rats were pretreated by oral gavage with 1, 3, or 10 mg/kg/day of SB-525334 once a day. The following day, PAN was injected at 15 mg/100 g to the appropriate rats. Treatment groups continued to receive SB-525334. Ten days after PAN injection the rats were sacrificed, and blood, urine, and kidneys were collected at the termination point for analysis [1]. |
| 体外活性 | SB-525334（1 μM）在肾小管近端细胞中阻断了TGF-beta1诱导的Smad2/3的磷酸化和核内转移，并抑制了TGF-beta1在A498肾上皮癌细胞中诱导的纤溶酶原激活物抑制剂-1（PAI-1）及前胶原α1(I) mRNA表达的增加[1]。与SB525334的联合应用显著增强了在亲本细胞和耐古美替尼的胰腺癌细胞中古美替尼的细胞毒性。SB525334在耐古美替尼的细胞中显著增加了凋亡细胞死亡[2]。 |
| 体内活性 | 口服给予1、3或10 mg/kg/day的SB 525334，连续11天，能显著降低肾脏PAI-1 mRNA表达[1]。SB 525334（10 mg/kg或30 mg/kg）每日两次口服。在Bleomycin（BLM）处理后的第5、7、9和14天，分离肺部进行研究。BLM处理导致显著的肺纤维化变化，伴随ECM mRNA表达显著上调、Smad2/3核转位、CTGF表达增加、肌成纤维细胞增殖以及I型胶原沉积。SB 525334处理减轻了肺部的组织病理学改变，并显著降低了I型和III型前胶原及纤维连接蛋白mRNA表达[3]。 |
| 存储条件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| 溶解度 | DMSO : ＜1 mg/mL (insoluble or slightly soluble)
1eq. HCl : 34.3 mg/mL (100 mM)
|
| 关键字 | inhibit | Inhibitor | TGF-β Receptor | Transforming growth factor beta receptors | SB-525334 | SB 525334 |
| 相关产品 | Monocrotaline | Pirfenidone | Ceritinib | A 83-01 | Chromenone 1 | LY-364947 | BMP signaling agonist sb4 | Alectinib hydrochloride | SB-431542 | Galunisertib | Alantolactone | Hydrochlorothiazide |
| 相关库 | 抑制剂库 | 肿瘤免疫治疗小分子化合物库 | 经典已知活性库 | 已知活性化合物库 | 激酶抑制剂库 | NO PAINS 化合物库 | 癌细胞分化化合物库 | TGF-β/Smad靶点化合物库 | 膜蛋白靶向化合物库 | 酪氨酸激酶分子库 |
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