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J Biomol Screen ; 16(7): 724-33, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21521800

ABSTRACT

Transforming growth factor ß (TGF-ß) type I receptor (activin receptor-like kinase 5, ALK5) has been identified as a promising target for fibrotic diseases. To find a novel inhibitor of ALK5, the authors performed a high-throughput screen of a library of 420,000 compounds using dephosphorylated ALK5. From primary hits of 1521 compounds, 555 compounds were confirmed. In total, 124 compounds were then selected for follow-up based on their unique structures and other properties. Repeated concentration-response testing and final interference assays of the above compounds resulted in the discovery of a structurally novel ALK5 inhibitor (compound 8) (N-(thiophen 2-ylmethyl)-3-(3,4,5 trimethoxyphenyl)imidazo[1,2ß]pyridazin 6-amine) with a low IC(50) value of 0.7 µM. Compound 8 also inhibited the TGF-ß-induced nuclear translocation of SMAD with an EC(50) value of 0.8 µM. Kinetic analysis revealed that compound 8 inhibited ALK5 via mixed-type inhibition, suggesting that it may bind to ALK5 differently than other published adenosine triphosphate site inhibitors.


Subject(s)
High-Throughput Screening Assays , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Receptors, Transforming Growth Factor beta/antagonists & inhibitors , Adenosine Diphosphate/metabolism , Cell Line, Tumor , Computer Simulation , Fluorescence Resonance Energy Transfer , Fluoroimmunoassay , Humans , Kinetics , Molecular Conformation , Phosphorylation/drug effects , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/metabolism , Receptor, Transforming Growth Factor-beta Type I , Receptors, Transforming Growth Factor beta/metabolism , Smad Proteins/metabolism , Small Molecule Libraries/pharmacology , Transforming Growth Factor beta/pharmacology
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