Evaluating the antifibrotic potency of galunisertib in a human ex vivo model of liver fibrosis

Background and Purpose Liver fibrosis is a major cause of liver‐related mortality and, so far, no effective antifibrotic drug is available. Galunisertib, a TGF‐β receptor type I kinase inhibitor, is a potential candidate for the treatment of liver fibrosis. Here, we evaluated the potency of galunise...

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Published in:British journal of pharmacology 2017-09, Vol.174 (18), p.3107-3117
Main Authors: Luangmonkong, Theerut, Suriguga, Su, Bigaeva, Emilia, Boersema, Miriam, Oosterhuis, Dorenda, Jong, Koert P, Schuppan, Detlef, Mutsaers, Henricus A M, Olinga, Peter
Format: Article
Language:English
Subjects:
Animals
Bile
Collagen (type I)
Dose-Response Relationship, Drug
Enzyme inhibitors
Extracellular matrix
Fibrosis
Humans
Inhibition
Liver
Liver Cirrhosis - drug therapy
Liver Cirrhosis - metabolism
Male
Phosphorylation
Phosphorylation - drug effects
Procollagen
Pyrazoles - chemistry
Pyrazoles - pharmacology
Quinolines - chemistry
Quinolines - pharmacology
Rats
Rats, Wistar
Research Paper
Research Papers
Smad2 protein
Smad2 Protein - antagonists & inhibitors
Smad2 Protein - metabolism
Structure-Activity Relationship
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Summary:Background and Purpose Liver fibrosis is a major cause of liver‐related mortality and, so far, no effective antifibrotic drug is available. Galunisertib, a TGF‐β receptor type I kinase inhibitor, is a potential candidate for the treatment of liver fibrosis. Here, we evaluated the potency of galunisertib in a human ex vivo model of liver fibrosis. Experimental Approach Antifibrotic potency and associated mechanisms were studied ex vivo, using both healthy and cirrhotic human precision‐cut liver slices. Fibrosis‐related parameters, both transcriptional and translational level, were assessed after treatment with galunisertib. Key Results Galunisertib showed a prominent antifibrotic potency. Phosphorylation of SMAD2 was inhibited, while that of SMAD1 remained unchanged. In healthy and cirrhotic human livers, spontaneous transcription of numerous genes encoding collagens, including collagen type I, α 1, collagen maturation, non‐collageneous extracellular matrix (ECM) components, ECM remodelling and selected ECM receptors was significantly decreased. The reduction of fibrosis‐related transcription was paralleled by a significant inhibition of procollagen I C‐peptide released by both healthy and cirrhotic human liver slices. Moreover, galunisertib showed similar antifibrotic potency in human and rat lives. Conclusions and Implications Galunisertib is a drug that deserves to be further investigated for the treatment of liver fibrosis. Inhibition of SMAD2 phosphorylation is probably a central mechanism of action. In addition, blocking the production and maturation of collagens and promoting their degradation are related to the antifibrotic action of galunisertib.
ISSN:0007-1188
1476-5381
DOI:10.1111/bph.13945