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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Inhibition of Gene Markers of Fibrosis with a Novel Inhibitor of Transforming Growth Factor- Type I Receptor Kinase in Puromycin-Induced Nephritis

Urogenital Biology, GlaxoSmithKline, King of Prussia, Pennsylvania (E.T.G., W.M.M., C.T., P.T., D.P.B., N.J.L.); and Cardiovascular and Urogenital Medicinal Chemistry, GlaxoSmithKline, Stevenage, United Kingdom (J.H.)

SB-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-1 (TGF-1) receptor, activin receptor-like kinase (ALK5). The compound inhibited ALK5 kinase activity with an IC₅₀ of 14.3 nM and was 4-fold less potent as an inhibitor of ALK4 (IC₅₀ = 58.5 nM). SB-525334 was inactive as an inhibitor of ALK2, ALK3, and ALK6 (IC₅₀ > 10,000 nM). In cell-based assays, SB-525334 (1 µM) blocked TGF-1-induced phosphorylation and nuclear translocation of Smad2/3 in renal proximal tubule cells and inhibited TGF-1-induced increases in plasminogen activator inhibitor-1 (PAI-1) and procollagen 1(I) mRNA expression in A498 renal epithelial carcinoma cells. In view of this profile, SB-525334 was used to investigate the role of TGF-1 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 1(I) and procollagen 1(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-1 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.

Address correspondence to: Eugene T. Grygielko, Urogenital Biology, UW2521, GlaxoSmithKline, 709 Swedeland Road, POB 1539, King of Prussia, PA 19406. E-mail: eugene_t_grygielko{at}gsk.com

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