Inhibition of TGF-beta signaling by an ALK5 inhibitor protects rats from dimethylnitrosamine-induced liver fibrosis.

Abstract

1 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.

• Authors: Anne-Charlotte de Gouville, Valerie Boullay, Gael Krysa, Julia Pilot, Jean-Marie Brusq, Florence Loriolle, Jean-Michel Gauthier, Stephen A Papworth, Alain Laroze, Françoise Gellibert, Stephane Huet
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 145 Issue 2 Pg. 166-77 (May 2005) ISSN: 0007-1188 [Print] England
• PMID: 15723089 (Publication Type: Journal Article)

Chemical References

• 2-phenyl-4-(3-pyridin-2-yl-1H-pyrazol-4-yl)pyridine
• Plasminogen Activator Inhibitor 1
• Pyrazoles
• Pyridines
• Receptors, Transforming Growth Factor beta
• Transforming Growth Factor beta
• Protein Serine-Threonine Kinases
• Activin Receptors, Type I
• Receptor, Transforming Growth Factor-beta Type I
• TGFBR1 protein, human
• Tgfbr1 protein, mouse
• Tgfbr1 protein, rat
• Dimethylnitrosamine

Topics

• Activin Receptors, Type I (antagonists & inhibitors, metabolism)
• Acute Disease
• Animals
• Cell Line, Tumor
• Chronic Disease
• Dimethylnitrosamine
• Hepatectomy
• Humans
• Liver Cirrhosis (chemically induced, pathology, prevention & control)
• Liver Regeneration (drug effects)
• Male
• Mice
• Mice, Transgenic
• Phosphorylation
• Plasminogen Activator Inhibitor 1 (biosynthesis, genetics)
• Protein Serine-Threonine Kinases
• Pyrazoles (pharmacology)
• Pyridines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptor, Transforming Growth Factor-beta Type I
• Receptors, Transforming Growth Factor beta (antagonists & inhibitors, metabolism)
• Signal Transduction
• Transcription, Genetic
• Transforming Growth Factor beta (antagonists & inhibitors, genetics, physiology)