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- Title
Small-molecule inhibitors of the PDZ domain of Dishevelled proteins interrupt Wnt signalling.
- Authors
Kamdem, Nestor; Roske, Yvette; Kovalskyy, Dmytro; Platonov, Maxim O.; Balinskyi, Oleksii; Kreuchwig, Annika; Saupe, Jörn; Liang Fang; Diehl, Anne; Schmieder, Peter; Krause, Gerd; Rademann, Jörg; Heinemann, Udo; Birchmeier, Walter; Oschkinat, Hartmut
- 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. Realtime 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.
- Subjects
WNT signal transduction; CANCER treatment; ANTI-inflammatory agents; SULINDAC; STRUCTURE-activity relationships; X-ray crystallography
- Publication
Magnetic Resonance, 2021, Vol 2, Issue 1, p355
- ISSN
2699-0016
- Publication type
Article
- DOI
10.5194/mr-2-355-2021