Screening and Identification of a Novel Class of TGF-β Type 1 Receptor Kinase Inhibitor
| Autor: | Erinn E. Pagratis, Benjamin A. Turner, Xiaohong Liu, Kelly R. Pitts, Q. Khai Huynh, Nikos Pagratis, Laurie A. Castonguay, Sarah Wise, David Koditek, Christopher B. Glascock, Keith A. Koch, Brian Reid, Magdeleine Hung, Bin Han |
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| Rok vydání: | 2011 |
| Předmět: |
Fluoroimmunoassay
Molecular Conformation Receptor Transforming Growth Factor-beta Type I Smad Proteins Protein Serine-Threonine Kinases Mitogen-activated protein kinase kinase Biochemistry Analytical Chemistry MAP2K7 Small Molecule Libraries Growth factor receptor Transforming Growth Factor beta Cell Line Tumor Fluorescence Resonance Energy Transfer Humans Computer Simulation Phosphorylation Protein Kinase Inhibitors biology Cyclin-dependent kinase 4 Chemistry Cyclin-dependent kinase 2 Molecular biology High-Throughput Screening Assays Adenosine Diphosphate Kinetics biology.protein Molecular Medicine Cyclin-dependent kinase 9 Receptors Transforming Growth Factor beta Platelet-derived growth factor receptor ACVR2B Biotechnology |
| Zdroj: | SLAS Discovery. 16:724-733 |
| ISSN: | 2472-5552 |
| DOI: | 10.1177/1087057111405846 |
| Popis: | Transforming growth factor β (TGF-β) 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[1,2β]pyridazin 6-amine) with a low IC(50) value of 0.7 µM. Compound 8 also inhibited the TGF-β-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. |
| Databáze: | OpenAIRE |
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