IWR-1-endo

Wnt signaling proteins are small secreted proteins that are active in embryonic development, tissue homeostasis, and tumorigenesis.{17947,14336,13185} Wnt proteins bind to receptors on the cell surface, initiating a signaling cascade that leads to ?-catenin activation of gene transcription. IWR-1-endo is a potent inhibitor of the Wnt response, blocking a cell-based Wnt/?-catenin pathway reporter response with an IC50 value of 180 nM.{17505} It inhibits, at 10 ?M, Wnt-induced accumulation of ?-catenin, leading to proteasomal degradation of this protein through a destruction complex which consists of Apc, Axin2, Ck1, and GSK3?. IWR-1-endo stabilizes the destruction complex, increasing the level of Axin2 protein without changing the levels of Apc or GSK3?.{17505} The IWR compound does not change the de novo synthesis of Axin2, alter the affinity of Axin2 for ?-catenin, or inhibit the proteasome. It has a half-life of 60 minutes in murine whole blood and 20 minutes in intact murine hepatocytes.{17948} In in vivo tests, IWR-1-endo inhibits zebrafish tail fin regeneration with a minimum inhibitory concentration of 0.5 ?M.{17948} The IWR-1-exo diastereomer exhibits much less activity against the Wnt/?-catenin pathway and has been used as a control.{17505}