title: Targeting the Tcf4 G13ANDE17 binding site to selectively disrupt β-catenin/T-cell factor protein-protein interactions.
abstract: Selective disruption of protein-protein interactions by small molecules is important for probing the structure and dynamic aspects of cellular network. It can also provide new therapeutic targets. β-Catenin of the canonical Wnt signaling pathway uses the same positively charged groove to bind with T-cell factor (Tcf), cadherin, and adenomatous polysis coli (APC). The extravagant formation of β-catenin/Tcf interactions drives the initiation and progression of many cancers and fibroses, while β-catenin/cadherin and β-catenin/APC interactions are essential for cell-cell adhesion and β-catenin degradation. In this study, a selective binding site that can differentiate β-catenin/Tcf, β-catenin/cadherin, and β-catenin/APC interactions was identified by alanine scanning and biochemical assays. A new peptidomimetic strategy that incorporates SiteMap and multiple-copy simultaneous search was used to design selective small-molecule inhibitors for β-catenin/Tcf interactions. A potent inhibitor was discovered to bind with β-catenin and completely disrupt β-catenin/Tcf interactions. It also exhibits dual selectivity for β-catenin/Tcf over β-catenin/cadherin and β-catenin/APC interactions in both biochemical and cell-based assays. This study provides a proof of concept for designing selective inhibitors for β-catenin/Tcf interactions.
authors.affiliation: Department of Chemistry, Center for Cell and Genome Science, University of Utah , Salt Lake City, Utah 84112-0850, United States.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Huang
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Shawn D
authors.initials: SD
authors.lastname: Burton
authors.forename: Levon N
authors.initials: LN
authors.lastname: Katsakhyan
authors.forename: Haitao
authors.initials: H
authors.lastname: Ji
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites / Q000187:drug effects; D015820:Cadherins / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D057786:Peptidomimetics / Q000737:chemistry / Q000494:pharmacology*; D060066:Protein Interaction Maps / Q000187:drug effects*; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D051176:beta Catenin / Q000737:chemistry / Q000378:metabolism*
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D015820:Cadherins; D057786:Peptidomimetics; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051176:beta Catenin