Inhibition of ALK5 as a new approach to treat liver fibrotic diseases.
Liver fibrosis is the result of an unbalanced wound healing response to a chronic hepatic injury. Transforming growth factor-beta (TGF-beta) plays a major role in this process via the activation of hepatic stellate cells. Various approaches have been tested in animal models of fibrosis to block the effects of TGF-beta, including antibodies and soluble receptors. Here, we discuss the potential use of TGF-beta signaling inhibitors, acting at the TGF-beta type I receptor kinase (ALK5) level, as a possible therapy for liver fibrosis. Thus far, there is only one ALK5 inhibitor (GW6604) for which activity in models of liver fibrosis has been described, showing clear antifibrotic effects resulting in liver function improvement. However, due to the pleiotropic effects of TGF-beta, the beneficial antifibrotic effects of ALK5 inhibition should be carefully balanced against the potential risk of unwanted effects stemming from chronic treatment.
de Gouville
Anne-Charlotte
AC
Biology Department, Glaxo-SmithKline Pharmaceuticals, Les Ulis, France. annecharlotte.m.degouville@gsk.com
Huet
Stephane
S
D030201:Activin Receptors, Type I / Q000037:antagonists & inhibitors*; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases; D011720:Pyrazoles / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D016212:Transforming Growth Factor beta / Q000502:physiology
C502971:2-phenyl-4-(3-pyridin-2-yl-1H-pyrazol-4-yl)pyridine; 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