SB-525334 is a potent and selective inhibitor of the transforming growth factor-beta1 (TGF-beta1) receptor, activin receptor-like kinase (ALK5). In cell-based assays, SB-525334 (1 microM) blocked TGF-beta1-induced phosphorylation and nuclear translocation of Smad2/3 in renal proximal tubule cells and inhibited TGF-beta1-induced increases in plasminogen activator inhibitor-1 (PAI-1) and procollagen alpha1(I) mRNA expression in A498 renal epithelial carcinoma cells. SB-525334 inhibited ALK5 kinase activity with an IC50 of 14.3 nM and was approximately 4-fold less potent as an inhibitor of ALK4 with IC50 of 58.5 nM. SB-525334 significantly increased apoptotic cell death in gemcitabine-resistant cells. SB-525334 reverses pulmonary arterial pressure and inhibits right ventricular hypertrophy in a rat model of PAH effectively. SB-525334 treatment showed significant attenuation in Smad2/3 nuclear translocation, decrease in CTGF-expressing cells, myofibroblast proliferation and type I collagen deposition.
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|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.
|Solubility||DMSO 60 mg/mL
Ethanol 60 mg/mL
|Source||Am J Physiol Renal Physiol (2015). Figure 4. SB-525334|
|Results||Aortic endothelial cell lysates obtained from the four groups of rats on day 7 of the experiment demonstrated activation of ALK5 by HS intake as well as the anticipated inhibition of ALK5 by SB-525334|
Activin-like kinase 5 (ALK5) mediates abnormal proliferation of vascular smooth muscle cells from patients with familial pulmonary arterial hypertension and is involved in the progression of experimental pulmonary arterial hypertension induced by monocrotaline.
Thomas M, et al. Am J Pathol. 2009 Feb;174(2):380-9. PMID: 19116361.
Tumor-specific efficacy of transforming growth factor-beta RI inhibition in Eker rats.
Laping NJ, et al. Clin Cancer Res. 2007 May 15;13(10):3087-99. PMID: 17505012.
Inhibition of activin receptor-like kinase 5 attenuates bleomycin-induced pulmonary fibrosis.
Higashiyama H, et al. Exp Mol Pathol. 2007 Aug;83(1):39-46. PMID: 17274978.
Inhibition of gene markers of fibrosis with a novel inhibitor of transforming growth factor-beta type I receptor kinase in puromycin-induced nephritis.
Grygielko ET, et al. J Pharmacol Exp Ther. 2005 Jun;313(3):943-51. PMID: 15769863.
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