Author/Authors :
Dae-Kee Kim، نويسنده , , Yeon-Im Lee، نويسنده , , Yeon-Woo Lee، نويسنده , , Purushottam M. Dewang، نويسنده , , Yhun Yhong Sheen، نويسنده , , Yeo Woon Kim، نويسنده , , Hyun-Ju Park، نويسنده , , Jakyung Yoo، نويسنده , , Ho Soon Lee، نويسنده , , Yong-Kook Kim، نويسنده ,
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.
