SB525334

SB525334 is a potent and selective inhibitor of TGFβ receptor I (ALK5) with IC50 of 14.3 nM in a cell-free assay, is 4-fold less potent to ALK4 than ALK5 and inactive to ALK2, 3, and 6.

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SB525334 Chemical Structure

SB525334 Chemical Structure
Molecular Weight: 343.42

Validation & Quality Control

Customer Product Validation(5)

Quality Control & MSDS

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Product Description

Biological Activity

Description SB525334 is a potent and selective inhibitor of TGFβ receptor I (ALK5) with IC50 of 14.3 nM in a cell-free assay, is 4-fold less potent to ALK4 than ALK5 and inactive to ALK2, 3, and 6.
Targets TGFβR1(ALK5) [1]
(Cell-free assay)
IC50 14.3 nM
In vitro SB 525334 shows no inhibition in the enzymes ALK2, 3, and 6, with IC50 values > 10 μM. SB 525334 blocks phosphorylation induced by TGF-β1 and nuclear translocation of Smad2/3 in renal proximal tubule cells. SB 525334 also inhibits the increased mRNA expression levels of plasminogen activator inhibitor-1 (PAI-1) and procollagen α1(I) induced by TGF-β1 in A498 renal epithelial carcinoma cells at 1 μM). [1] SB 525334 (1 μM) attenuates the heightened sensitivity to TGF-β1 exhibited by pulmonary artery smooth muscle cells (PASMCs) from patients with familial forms of idiopathic pulmonary arterial hypertension (PAH). [2]
In vivo SB 525334 (10 mg/kg/day) decreases the renal mRNA levels of PAI-1, procollagen α1(I), and procollagen α1(III) in a nephritis-induced renal fibrosis rat model. Furthermore, PAN-induced proteinuria is significantly inhibited by SB 525334 (10 mg/kg/day). [1] SB 525334 may also be efficacious in mesenchymal tumors. SB 525334 (10 mg/kg/day) significantly decreases uterine mesenchymal tumor incidence, multiplicity, and size in Eker rats. [3] SB 525334 significantly reverses pulmonary arterial pressure and inhibits right ventricular hypertrophy in a rat model of PAH. This is revealed by a significant reduction in pulmonary arteriole muscularization induced by monocrotaline (used to induce PAH) after treatment with SB 525334 (3 or 30 mg/kg). [2] In a Bleomycin-induced pulmonary fibrosis mice model, SB 525334 (10 mg/kg or 30 mg/kg) attenuates the histopathological alterations in the lung, and significantly decreased mRNA expression of Type I and III procollagen and fibronectin. SB 525334 also attenuates Smad2/3 nuclear translocation, myofibroblast proliferation, deposition of Type I collagen, and decreases CTGF-expressing cells. [4]
Features

Protocol(Only for Reference)

Kinase Assay: [1]

Kinase assay to determine the potency and selectivity of SB 525334 In order to determine the potency of SB 525334, purified GST-tagged kinase domain of ALK5 is incubated with purified GST-tagged full-length Smad3 in the presence of 33P-γATP and different concentrations of SB 525334. The readout is radioactively labeled Smad3. To determine the selectivity of SB 525334, purified GST-tagged kinase domain of ALK2 and ALK4 are incubated with GST-tagged full-length Smad1 and Smad3, respectively, in the presence of different concentrations of SB 525334. IC50 values are calculated.

Cell Assay: [1]

Cell lines Human renal proximal tubule epithelial (RPTE) cells
Concentrations 1 μM
Incubation Time 1 hour
Method RPTE cells are seeded on microscope slides. The following day, the cells are starved for 24 hours to dosing by removal of the serum and epidermal growth factor. Cells are treated with either 10 ng/mL TGF-β1, 1 μM SB 525334, or a combination of both. Slides are pretreated with SB 525334 or starve media for 3 hours prior to a 1-hour incubation at 37 °C with TGF-β1 or starve media. The cells are then fixed and permeabilized. The slides are blocked with BSA, incubated with a mouse anti-Smad2/3 primary antibody followed by an anti-mouse IgG fluorescein secondary antibody. The slides are then viewed in a confocal microscope and nuclear signal intensity is analyzed.

Animal Study: [3]

Animal Models Bleomycin-induced pulmonary fibrosis in female Eker rats
Formulation 200 mg/L in drinking water
Dosages Estimated dose of 10 mg/kg/day
Administration Oral (in drinking water)

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDogMonkeyBaboon
Weight (kg)0.020.151.80.40.0810312
Body Surface Area (m2)0.0070.0250.150.050.020.50.240.6
Km factor361285201220
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Grygielko ET, et al. J Pharmacol Exp Ther, 2005, 313(3), 943-951.

[2] Thomas M, et al. Am J Pathol, 2009, 174(2), 380-389.

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Chemical Information

Download SB525334 SDF
Molecular Weight (MW) 343.42
Formula

C21H21N5

CAS No. 356559-20-1
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 68 mg/mL (198.0 mM)
Ethanol 68 mg/mL (198.0 mM)
Water <1 mg/mL (<1 mM)
In vivo 30% propylene glycol, 5% Tween 80, 65% D5W 20 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name 6-(2-tert-butyl-4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl)quinoxaline

Research Area

Customer Product Validation (5)


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Rating
Source Hypertension 2013 62(5), 951-6. SB525334 purchased from Selleck
Method Western blot
Cell Lines aortic endothelial cells
Concentrations 10 mg/kg/d
Incubation Time 2 days
Results Four groups of rats were studied. The first two groups were fed the 0.3% NaCl diet and given either vehicle or SB525334, which inhibits TβRI/ALK5, two days before the end of the experiment. The second two groups received the 8.0% NaCl diet and either vehicle or SB525334 two days before the end of the experiment. An increase in dietary salt intake increased p-Smad2(S465/467) in endothelial lysates; this increase was inhibited by treatment with SB525334. Increased salt intake also decreased endothelial PTEN levels and increased p-Akt(S473) without changing total Akt levels; treatment with SB525334 prevented these salt-induced changes in PTEN and p-Akt(S473). The dietary salt-induced relative increase in p-NOS3(S1177), which increases NO production, was abrogated by treatment with SB525334.

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Rating
Source Cancer Lett 2014 355(1), 130-40. SB525334 purchased from Selleck
Method Immunoblotting
Cell Lines LS 174T, SW480 cells
Concentrations 1 uM
Incubation Time 12 h
Results The treatment of cells with SB525334, a specific inhibitor of the kinase activity of TGF-β family receptor I, significantly reduced HMGA2 expression in Smad4-expressing cells (LS 174T and SW480) detected by immunoblots.

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Rating
Source Cell Signal 2014 10.1016/j.cellsig.2014.09.010. SB525334 purchased from Selleck
Method Immunofluorescent
Cell Lines LS 174T, SW480 cells
Concentrations 1 uM
Incubation Time 72 h
Results The NRK-52E cell line is a well-characterized model of epithelial to mesenchymal or myofibroblast transition (MT). AGEs induce a myofibroblast phenotype in these cells that is dependent on TGF-β expression. Both the ERK inhibitor PD98059 (PD, 1 uM) and the TGF-β receptor kinase inhibitor SB525334 (SB, 1 uM) appeared to prevent this transition (G and H). Finally, the addition of the AT1 receptor antagonist losartan (I) did not appear to attenuate α-SMA in comparison to treatment with Ang-(1–7), PD or SB.

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Rating
Source Cell Signal 2014 10.1016/j.cellsig.2014.09.010. SB525334 purchased from Selleck
Method Immunoblotting
Cell Lines Chondrocytes
Concentrations 1 uM
Incubation Time 1 h
Results To further investigate the involvement of the ERK1/2 and Smad2/3 signaling pathways in TGF-β1-induced TIMP-3 expression, chondrocytes were pre-treated with TGF-β receptor I (ALK5) kinase inhibitor, SB525334, for 60 min and then stimulated with or without 10 ng/ml of TGF-β1 for 48 h. Real-time PCR and western blotting confirmed that TGF-β1 stimulated TIMP-3 expression was inhibited by SB525334.

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Rating
Source SB525334 purchased from Selleck
Method ALP assay/Quantitative RT-PCR
Cell Lines C3H10T1/2 cells
Concentrations 10 μM
Incubation Time
Results Cotreatment with SB-431542 or SB-525334 has not only inhibited ALP activities compared with vehicle treatment but also abrogated the TAZ-mediated enhancement of ALP activities.

Product Use Citation (7)

Tech Support & FAQs

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