Small-molecule Inhibitors of the PDZ Domain of Dishevelled Proteins Interrupt Wnt Signalling

Overview

Journal Magn Reson (Gott)

Date 2023 Oct 31

PMID 37904770

Authors

Nestor Kamdem

Yvette Roske

Dmytro Kovalskyy

Maxim O Platonov

Oleksii Balinskyi

Annika Kreuchwig

Jorn Saupe

Liang Fang

Anne Diehl

Peter Schmieder

Gerd Krause

Jorg Rademann

Udo Heinemann

Walter Birchmeier

Hartmut Oschkinat

Affiliations

Soon will be listed here.

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 ) and Western blotting of -catenin levels. Real-time PCR showed reduction in the expression of Wnt-specific genes. Our compound interacted with Dvl-1 PDZ (K ) stronger than Ky-02327 and may be developed into a lead compound interfering with the Wnt pathway.

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