Fig. 5

Schematic representation of Wnt pathway inhibition by small molecule inhibitors. Wnt pathway is turned off in the absence of Wnt ligand (left); destruction complex involving APC, Axin-1, and GSK-3β interacts with and phosphorylates β-catenin leading to its degradation. Binding of Wnt ligands to their cognate Frizzled (FZD) receptors and its co-receptors, low density lipoprotein receptor related proteins 5/6 (LRP5/6), activates the Wnt pathway (right) leading to sequestration and degradation of Axin-1 and phosphorylation and degradation of GSK-3β. Degradation of destruction complex components leads to accumulation of β-catenin and its subsequent translocation into the nucleus where it interacts with TCF4 to promote transcription of Wnt target genes. IWR1 stabilizes Axin-1 and promotes formation of destruction complex and degradation of β-catenin (red arrows). IWP2 inhibits Porcupine-mediated acylation and subsequent secretion of Wnt ligands. XAV939 inhibits Tankyrase-mediated degradation of Axin-1 and thus promotes formation of destruction complex (red dashed arrow). CCT036477, iCRT14, and PKF118-310 target β-catenin-TCF4 transcription complex