Small-molecule inhibitors of the PDZ domain of Dishevelled proteins interrupt Wnt signalling

Abstract

Abstract. Dishevelled (Dvl) proteins are important regulators of the Wnt signalling\npathway, interacting through their PDZ domains with the Wnt receptor\nFrizzled. Blocking the Dvl PDZ–Frizzled interaction represents a potential\napproach for cancer treatment, which stimulated the identification of small-molecule inhibitors, among them the anti-inflammatory drug Sulindac and\nKy-02327. Aiming to develop tighter binding compounds without side effects,\nwe investigated structure–activity relationships of sulfonamides. X-ray\ncrystallography showed high complementarity of anthranilic acid derivatives\nin the GLGF loop cavity and space for ligand growth towards the PDZ surface. Our best binding compound inhibits Wnt signalling in a dose-dependent manner as demonstrated by TOP-GFP assays (IC 50∼50 µM ) and Western blotting of β -catenin levels. Real-time PCR showed reduction in the expression of Wnt-specific genes. Our compound interacted with Dvl-1 PDZ (K D=2.4 µM ) stronger than Ky-02327 and may be developed into a lead compound interfering with the Wnt pathway.