SB525334

Catalog No.S1476

SB525334 is a potent and selective inhibitor of TGFβ receptor I (ALK5) with IC50 of 14.3 nM in a cell-free assay, 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

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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, 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]
Cell Data
Cell LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
rhPOSTNMYHBdI9xfG:|aYOgRZN{[Xl?M2nBUlAvPcLizszNxsA>MmHvOFjDqGh?M{Lo[5Nq\26rZnnjZY51dHliZHXjdoVie2W|IITo[UBvfW2kZYKgc4Yh[XCxcITveIlkKGOnbHzzMVWyOFEzQTF6OB?=
HUVECsMoTuSpVv[3Srb36gRZN{[Xl?M3i4ZVExKM7:TR?=NHrYeHIzPC92OD:3NkBpNXz4eYpudGWjZIOgeI8h[SCmaYPyeZB1cW:wIH;mJJRp\SCKVW\FR{Bud26xbHH5[ZIh[W[2ZYKgO|IhcHJ?NUPCdlJEOjN7Nki5PFE>
HUVECsMWjGeY5kfGmxbjDBd5NigQ>?M3n5OlExKM7:TR?=MX23NkBpNIfkOHpjdG:la4Ogd4lodmGuaX7nM3zmUVI{QTZ6OUix
HUVECsNGe3T4hHfW6ldHnvckBCe3OjeR?=MnTJNVAh|ryPNFTUdmw4OiCqMUHy[YR2[2W|IITo[UBxcG:|cHjvdplt[XSrb36gc4Yhe22jZEK=MkjFNlM6Pjh7OEG=
MiaPaCa2MUHD[YxtKF[rYXLpcIl1gSCDc4PhfS=>MVOwMVExKM7:TR?=MYC3NkBpMn\I[YZncWOrZX70cJkhemWmdXPld{B1cGVidnnhZoltcXS7IIfpeIgh\2WvY3n0ZYJqdmV?M{LqR|IzOzl7NUm3
AsPC1NGLB[WRE\WyuIG\pZYJqdGm2eTDBd5NigQ>?MY[wMVExKM7:TR?=MYm3NkBpNEjYZ4pm\m[rY3nlcpRtgSC{ZXT1Z4V{KHSqZTD2bYFjcWyrdImge4l1cCCpZX3jbZRi[mmwZR?=M4q2e|IzOzl7NUm3
PASMCs MlG2SpVv[3Srb36gRZN{[Xl?NILISZAyKM7:TR?=NWPobXZ2OTVibXnuM2iwVolvcGmkaYTzJHRITi4QskGtcYVlcWG2ZXSgdJJwdGmoZYLheIlwdiCxZjDmZY1qdGmjbDDpVGFJKFCDU13Dd{BifCCjbjDJR|UxyqCxZjCyPVUhdm2xbD;MMnqzNVkyOTZ|NkG=
ELT-3 M{i3T2Z2dmO2aX;uJGF{e2G7MnrtNE42NzFwMD:yMlAh|ryPMWKxJIg>M1nPb2ROW09?NH:yVGRqdmirYnn0d{BVT0ZvzsKgd4lodmGuaX7nJIlvKGynaX;tfY9u[XN?MVOxO|UxPTBzMh?=

... Click to View More Cell Line Experimental Data

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 pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
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
2 years -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
In vivo 5% DMSO+corn oil 20mg/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

Frequently Asked Questions

  • Question 1
    I want to know the feasibility of using the compound via oral gavage in rodents (dosing, frequency, formulation…)?

    Answer: Our S1476 can be used for oral gavage in rodents, and the vehicle we suggest is: 30% Propylene glycol, 5% Tween 80, 65% D5W (dextrose(5%)in water) at 20mg/ml maximum. Based on the following reference they administrated it at an estimated dose of 10 mg/kg/day in rat for 2 months: http://clincancerres.aacrjournals.org/content/13/10/3087.long

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Tel: +1-832-582-8158 Ext:3

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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