title: Small-molecule inhibitors of AF6 PDZ-mediated protein-protein interactions.
abstract: 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.
authors.affiliation: Leibniz Institute of Molecular Pharmacology (FMP), Robert-Rössle-Str. 10, 13125 Berlin (Germany); Current address: Molecular Biophysics, University of Kaiserslautern, Erwin-Schrödinger-Str. 13, 67663 Kaiserslautern (Germany).
authors.forename: Carolyn
authors.initials: C
authors.lastname: Vargas
authors.forename: Gerald
authors.initials: G
authors.lastname: Radziwill
authors.forename: Gerd
authors.initials: G
authors.lastname: Krause
authors.forename: Anne
authors.initials: A
authors.lastname: Diehl
authors.forename: Sandro
authors.initials: S
authors.lastname: Keller
authors.forename: Nestor
authors.initials: N
authors.lastname: Kamdem
authors.forename: Constantin
authors.initials: C
authors.lastname: Czekelius
authors.forename: Annika
authors.initials: A
authors.lastname: Kreuchwig
authors.forename: Peter
authors.initials: P
authors.lastname: Schmieder
authors.forename: Declan
authors.initials: D
authors.lastname: Doyle
authors.forename: Karin
authors.initials: K
authors.lastname: Moelling
authors.forename: Volker
authors.initials: V
authors.lastname: Hagen
authors.forename: Markus
authors.initials: M
authors.lastname: Schade
authors.forename: Hartmut
authors.initials: H
authors.lastname: Oschkinat
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008024:Ligands; D062105:Molecular Docking Simulation; D009218:Myosins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054731:PDZ Domains; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D036183:Receptor, EphB2 / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C095516:AFDN protein, human; D008024:Ligands; D010455:Peptides; D054852:Small Molecule Libraries; D036183:Receptor, EphB2; D009218:Myosins; D016547:Kinesins
keywords: NMR spectroscopy; chemical shift perturbation; chemical synthesis; molecular modeling; signal transduction