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 pathway, interacting through their PDZ domains with the Wnt receptor Frizzled. Blocking the Dvl PDZ/Frizzled interaction represents a potential approach for cancer treatment, which stimulated the identification of small molecule inhibitors, among them the anti-inflammatory drug Sulindac and Ky-02327. Aiming to develop tighter binding compounds without side effects, we investigated structure-activity relationships of sulfonamides. X-ray crystallography showed high complementarity of anthranilic acid derivatives in 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 (IC50 ~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 (Kd = 2.4 µM) stronger than Ky-02327 and may be developed into a lead compound interfering with the Wnt pathway.

Targeting peptide‐mediated interactions in omics

“…There were only very few published works about discovery of competitive antagonists targering PMIs. Most were developed for small PRDs by random screening and structure-directed optimization, such as the SH3 domain-mediated PMI-blocking drugs [79] and metallocompounds [80] as well as PDZ domain-mediated PMI inhibitors [81,82]. Besides, Xu et al have reported a method termed peptide scaffold-based discovery of nonpeptide medicines to target PRDmediated PMIs, who extracted the core binding motif of a SH2 domain-cocrystallized phosphopeptide to serve as the basic scaffold and then performed high-throughput virtual screening against a druglike compound library to identify the hits with high binding potency to the domain and significant conformational similarity with the peptide scaffold, which were also demonstrated to be able to compete with peptide partners for the domain [83].…”