SB-525334

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.