Abstract
A series of 4(5)-(6-methylpyridin-2-yl)imidazoles 16-19 and -pyrazoles 22-29, 33, and 34 have been synthesized and evaluated for their ALK5 inhibitory activity in an enzyme assay and in cell-based luciferase reporter assays. The 6-quinolinyl imidazole analogs 16 and 18 inhibited ALK5 phosphorylation with IC50 values of 0.026 and 0.034 μM, respectively. In a luciferase reporter assay using HaCaT cells transiently transfected with p3TP-luc reporter construct, 18 displayed 66% inhibition at 0.05 μM, while competitor compounds 2 and 3 showed 44% inhibition. The binding mode of 18 generated by flexible docking studies with ALK5:18 complex shows that it fits well into the active site cavity of ALK5 by forming broad and tight interactions.
Original language | English |
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Pages (from-to) | 4459-4467 |
Number of pages | 9 |
Journal | Bioorganic and Medicinal Chemistry |
Volume | 18 |
Issue number | 12 |
DOIs | |
State | Published - 15 Jun 2010 |
Bibliographical note
Funding Information:This work was supported by a grant from Ministry of Commerce, Industry and Energy, Korea ( 10027900 ).
Keywords
- ALK5 inhibitor
- Cell-based luciferase reporter assays
- TGF-β