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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; Martin WM; Tweed C; Thornton P; Harling J; Brooks DP; Laping NJJ Pharmacol Exp Ther 2005[Jun]; 313 (3): 943-51SB-525334 (6-[2-tert-butyl-5-(6-methyl-pyridin-2-yl)-1H-imidazol-4-yl]-quinoxaline) has been characterized as a potent and selective inhibitor of the transforming growth factor-beta1 (TGF-beta1) receptor, activin receptor-like kinase (ALK5). The compound inhibited ALK5 kinase activity with an IC(50) of 14.3 nM and was approximately 4-fold less potent as an inhibitor of ALK4 (IC(50) = 58.5 nM). SB-525334 was inactive as an inhibitor of ALK2, ALK3, and ALK6 (IC(50) > 10,000 nM). 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. In view of this profile, SB-525334 was used to investigate the role of TGF-beta1 in the acute puromycin aminonucleoside (PAN) rat model of renal disease, a model of nephritis-induced renal fibrosis. Orally administered doses of 1, 3, or 10 mg/kg/day SB-525334 for 11 days produced statistically significant reductions in renal PAI-1 mRNA. Also, the compound produced dose-dependent decreases in renal procollagen alpha1(I) and procollagen alpha1(III) mRNA, which reached statistical significance at the 10-mg/kg/day dose when compared with vehicle-treated PAN controls. Furthermore, PAN-induced proteinuria was significantly inhibited at the 10-mg/kg/day dose level. These results provide further evidence for the involvement of TGF-beta1 in the profibrotic changes that occur in the PAN model and for the first time, demonstrate the ability of a small molecule inhibitor of ALK5 to block several of the markers that are predictive of fibrosis and renal injury in this model.|Activin Receptors/antagonists & inhibitors[MESH]|Animals[MESH]|Biomarkers[MESH]|Cell Line, Tumor[MESH]|Collagen Type I/genetics[MESH]|Dose-Response Relationship, Drug[MESH]|Fibrosis[MESH]|Humans[MESH]|Kidney/*pathology[MESH]|Nephritis/metabolism/*pathology[MESH]|Phosphorylation[MESH]|Plasminogen Activator Inhibitor 1/genetics[MESH]|Protein Serine-Threonine Kinases/*antagonists & inhibitors[MESH]|Puromycin/*toxicity[MESH]|RNA, Messenger/analysis[MESH]|Rats[MESH]|Rats, Sprague-Dawley[MESH]|Receptor, Transforming Growth Factor-beta Type I[MESH]|Receptors, Transforming Growth Factor beta[MESH]|Transforming Growth Factor beta/*antagonists & inhibitors/physiology[MESH]|Transforming Growth Factor beta1[MESH] |
