Small‐Molecule Inhibitors of AF6 PDZ‐Mediated Protein–Protein Interactions. Issue 7 (25th March 2014)

• Record Type: Journal Article
• Authors: Vargas, Carolyn; Radziwill, Gerald; Krause, Gerd; Diehl, Anne; Keller, Sandro; Kamdem, Nestor; Czekelius, Constantin; Kreuchwig, Annika; Schmieder, Peter; Doyle, Declan; Moelling, Karin; Hagen, Volker; Schade, Markus; Oschkinat, Hartmut
• Is Part Of: ChemMedChem. Volume 9:Issue 7(2014:Jul.)
• Page Start: 1458
• Page End: 1462
• Publication Date: 2014-03-25
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201300553
• Languages: English
• ISSNs: 1860-7179

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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.</p> </abstract>