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| Item Type: | Article |
|---|---|
| Title: | Small-molecule inhibitors of the PDZ domain of Dishevelled proteins interrupt Wnt signalling |
| Creators Name: | Kamdem, N. and Roske, Y. and Kovalskyy, D. and Platonov, M.O. and Balinskyi, O. and Kreuchwig, A. and Saupe, J. and Fang, L. and Diehl, A. and Schmieder, P. and Krause, G. and Rademann, J. and Heinemann, U. and Birchmeier, W. and Oschkinat, H. |
| 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 (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. |
| Source: | Magnetic Resonance |
| ISSN: | 2699-0016 |
| Publisher: | Copernicus Publications |
| Volume: | 2 |
| Number: | 1 |
| Page Range: | 355-374 |
| Date: | 2 June 2021 |
| Official Publication: | https://doi.org/10.5194/mr-2-355-2021 |
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