title: 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.affiliation: Biology Department, GlaxoSmithKline, 25 avenue du Quebec, Les Ulis 91951, France. m.degouville@gsk.com
authors.forename: Anne-Charlotte
authors.initials: AC
authors.lastname: de Gouville
authors.forename: Valerie
authors.initials: V
authors.lastname: Boullay
authors.forename: Gael
authors.initials: G
authors.lastname: Krysa
authors.forename: Julia
authors.initials: J
authors.lastname: Pilot
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Brusq
authors.forename: Florence
authors.initials: F
authors.lastname: Loriolle
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Gauthier
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Papworth
authors.forename: Alain
authors.initials: A
authors.lastname: Laroze
authors.forename: Françoise
authors.initials: F
authors.lastname: Gellibert
authors.forename: Stephane
authors.initials: S
authors.lastname: Huet
mesh_terms: D030201:Activin Receptors, Type I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000208:Acute Disease; D000818:Animals; D045744:Cell Line, Tumor; D002908:Chronic Disease; D004128:Dimethylnitrosamine; D006498:Hepatectomy; D006801:Humans; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D008115:Liver Regeneration / Q000187:drug effects; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology
chemical_list: C502971:2-phenyl-4-(3-pyridin-2-yl-1H-pyrazol-4-yl)pyridine; D017395:Plasminogen Activator Inhibitor 1; D011720:Pyrazoles; D011725:Pyridines; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse; C000625843:Tgfbr1 protein, rat; D004128:Dimethylnitrosamine
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