Sulindac Inhibits Canonical Wnt Signaling by Blocking the PDZ Domain of the Protein Dishevelled

PDZ (PSD-95, Dlg, ZO-1) domains are ubiquitous interaction modules that are involved in many cellular signal transduction pathways. Interference with PDZ-mediated protein-protein interactions has important implications in disease-related signaling processes. For this reason, PDZ domains have gained attention as potential targets for inhibitor design and, in the long run, drug development. Herein we report the development of small molecules to probe the function of the PDZ domain from human AF6 (ALL1-fused gene from chromosome 6), which is an essential component of cell-cell junctions. These compounds bind to AF6 PDZ with substantially higher affinity than the peptide (Ile-Gln-Ser-Val-Glu-Val) derived from its natural ligand, EphB2. In intact cells, the compounds inhibit the AF6-Bcr interaction and interfere with epidermal growth factor (EGF)-dependent signaling.

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Sulindac Inhibits Canonical Wnt Signaling by Blocking the PDZ Domain of the Protein Dishevelled

Cited by 4 publications

References 50 publications

Chemical and Structural Biology to Direct the Repurposing of Sulindac

Chemical and Structural Biology to Direct the Repurposing of Sulindac

An Old NSAID Revisited: Crystal Structure of Aldose Reductase in Complex with Sulindac at 1.0 Å Supports a Novel Mechanism for its Anticancer and Antiproliferative Effects

Small‐Molecule Inhibitors of AF6 PDZ‐Mediated Protein–Protein Interactions

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