Premium
Small‐Molecule Inhibitors of AF6 PDZ‐Mediated Protein–Protein Interactions
Author(s) -
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
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201300553
Subject(s) - pdz domain , microbiology and biotechnology , small molecule , signal transduction , scaffold protein , biology , protein–protein interaction , chemistry , biochemistry
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.