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

Abstract. Dishevelled (Dvl) proteins are important regulators of the Wnt signalling pathway, interacting through their PDZ domains with receptor Frizzled. Blocking Dvl PDZ–Frizzled interaction represents a potential approach for cancer treatment, which stimulated identification small-molecule inhibitors, among them anti-inflammatory drug Sulindac and Ky-02327. Aiming to develop tighter binding compounds without side effects, we investigated structure–activity relationships sulfonamides. X-ray crystallography showed high complementarity anthranilic acid derivatives in GLGF loop cavity space ligand growth towards surface. Our best compound inhibits dose-dependent manner as demonstrated by TOP-GFP assays (IC50∼50 µM) Western blotting β-catenin levels. Real-time PCR reduction expression Wnt-specific genes. interacted Dvl-1 (KD=2.4 stronger than Ky-02327 may be developed into lead interfering pathway.