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lüll Inhibition of TGF-beta signaling by an ALK5 inhibitor protects rats from dimethylnitrosamine-induced liver fibrosis de Gouville AC; Boullay V; Krysa G; Pilot J; Brusq JM; Loriolle F; Gauthier JM; Papworth SA; Laroze A; Gellibert F; Huet SBr J Pharmacol 2005[May]; 145 (2): 166-771 Chronic liver disease is characterized by an exacerbated accumulation of matrix, causing progressive fibrosis, which may lead to cirrhosis. Transforming growth factor beta (TGF-beta), a well-known profibrotic cytokine, transduces its signal through the ALK5 ser/thr kinase receptor, and increases transcription of different genes including PAI-1 and collagens. The identification of GW6604 (2-phenyl-4-(3-pyridin-2-yl-1H-pyrazol-4-yl)pyridine), an ALK5 inhibitor, allowed us to evaluate the therapeutic potential of inhibiting TGF-beta pathway in different models of liver disease. 2 A cellular assay was used to identify GW6604 as a TGF-beta signaling pathway inhibitor. This ALK5 inhibitor was then tested in a model of liver hepatectomy in TGF-beta-overexpressing transgenic mice, in an acute model of liver disease and in a chronic model of dimethylnitrosamine (DMN)-induced liver fibrosis. 3 In vitro, GW6604 inhibited autophosphorylation of ALK5 with an IC(50) of 140 nM and in a cellular assay inhibited TGF-beta-induced transcription of PAI-1 (IC(50): 500 nM). In vivo, GW6604 (40 mg kg(-1) p.o.) increased liver regeneration in TGF-beta-overexpressing mice, which had undergone partial hepatectomy. In an acute model of liver disease, GW6604 reduced by 80% the expression of collagen IA1. In a chronic model of DMN-induced fibrosis where DMN was administered for 6 weeks and GW6604 dosed for the last 3 weeks (80 mg kg(-1) p.o., b.i.d.), mortality was prevented and DMN-induced elevations of mRNA encoding for collagen IA1, IA2, III, TIMP-1 and TGF-beta were reduced by 50-75%. Inhibition of matrix genes overexpression was accompanied by reduced matrix deposition and reduction in liver function deterioration, as assessed by bilirubin and liver enzyme levels. 4 Our results suggest that inhibition of ALK5 could be an attractive new approach to treatment of liver fibrotic diseases by both preventing matrix deposition and promoting hepatocyte regeneration.|*Dimethylnitrosamine[MESH]|Activin Receptors, Type I/*antagonists & inhibitors/metabolism[MESH]|Acute Disease[MESH]|Animals[MESH]|Cell Line, Tumor[MESH]|Chronic Disease[MESH]|Hepatectomy[MESH]|Humans[MESH]|Liver Cirrhosis/chemically induced/pathology/*prevention & control[MESH]|Liver Regeneration/drug effects[MESH]|Male[MESH]|Mice[MESH]|Mice, Transgenic[MESH]|Phosphorylation[MESH]|Plasminogen Activator Inhibitor 1/biosynthesis/genetics[MESH]|Protein Serine-Threonine Kinases[MESH]|Pyrazoles/*pharmacology[MESH]|Pyridines/*pharmacology[MESH]|Rats[MESH]|Rats, Sprague-Dawley[MESH]|Receptor, Transforming Growth Factor-beta Type I[MESH]|Receptors, Transforming Growth Factor beta/*antagonists & inhibitors/metabolism[MESH]|Signal Transduction[MESH]|Transcription, Genetic[MESH]|Transforming Growth Factor beta/*antagonists & inhibitors/genetics/physiology[MESH] |