A potent inhibitor of TGF-β R1/ALK5 kinase
SB525334 is a potent inhibitor of transforming growth factor-beta1 (TGF-beta1) receptor, activin receptor-like kinase (ALK5). It specifically inhibits ALK5 with IC50 value of 14.3nM, which shows 4-fold higher potency against ALK4 [1].
SB525334 has been demonstrated to reduce smad2/3 nuclear fluorescence induced by TGF-beta1 in human renal proximal tubule epithelial (RPTE) cells. Additionally, SB525334 inhibits TGF-beta1 mediated procollagen and PAI-1 expression in human renal carcinoma cells A498 [1].
SB525334 dose-dependently reduces Urinary protein, procollagen alpha1(I) mRNA and procollagen alpha1(III) mRNA when administered orally in acute puromycin aminonucleoside (PAN) rat model of renal disease [1].
Reference:
[1] Grygielko ET1, Martin WM, Tweed C, Thornton P, Harling J, Brooks DP, Laping NJ.? Inhibition of gene markers of fibrosis with a novel inhibitor of transforming growth factor-beta type I receptor kinase in puromycin-induced nephritis. J Pharmacol Exp Ther. 2005 Jun;313(3):943-51.
| Kinase experiment [1]: | |
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Kinase assay |
To determine the potency of SB525334, 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 SB525334, 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 SB525334. IC50 values were calculated. |
| Cell experiment [1]: | |
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Cell lines |
Human renal proximal tubule epithelial (RPTE) cells |
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Preparation method |
The solubility of this compound in DMSO is > 10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20 °C for several months. |
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Reaction Conditions |
1 μM; 1 hr |
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Applications |
In RPTE cells, SB525334 reduced endogenous TGF-β1 signaling. |
| Animal experiment [2]: | |
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Animal models |
Bleomycin-induced pulmonary fibrosis in female Eker rats |
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Dosage form |
10 mg/kg/day; p.o. |
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Applications |
In Eker rats, SB525334 significantly decreased uterine mesenchymal tumor incidence, multiplicity and size. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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参考文献: [1]. Grygielko ET, Martin WM, Tweed C, Thornton P, Harling J, Brooks DP, Laping NJ. Inhibition of gene markers of fibrosis with a novel inhibitor of transforming growth factor-beta type I receptor kinase in puromycin-induced nephritis. J Pharmacol Exp Ther. 2005 Jun;313(3):943-51. [2]. Laping NJ, Everitt JI, Frazier KS, Burgert M, Portis MJ, Cadacio C, Gold LI, Walker CL. Tumor-specific efficacy of transforming growth factor-beta RI inhibition in Eker rats. Clin Cancer Res. 2007 May 15;13(10):3087-99. | |
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