title: Structure-Based Design of 1,4-Dibenzoylpiperazines as β-Catenin/B-Cell Lymphoma 9 Protein-Protein Interaction Inhibitors.
abstract: A small-molecule inhibitor with a 1,4-dibenzoylpiperazine scaffold was designed to match the critical binding elements in the β-catenin/B-cell lymphoma 9 (BCL9) protein-protein interaction interface. Inhibitor optimization led to a potent inhibitor that can disrupt the β-catenin/BCL9 interaction and exhibit 98-fold selectivity over the β-catenin/cadherin interaction. The binding mode of new inhibitors was characterized by structure-activity relationships and site-directed mutagenesis studies. Cell-based studies demonstrated that this series of inhibitors can selectively suppress canonical Wnt signaling and inhibit growth of Wnt/β-catenin-dependent cancer cells.
authors.affiliation: Department of Chemistry, Center for Cell and Genome Science, University of Utah , Salt Lake City, Utah 84112-0850, United States.
authors.forename: John A
authors.initials: JA
authors.lastname: Wisniewski
authors.affiliation: Department of Chemistry, Center for Cell and Genome Science, University of Utah , Salt Lake City, Utah 84112-0850, United States.
authors.forename: Jinya
authors.initials: J
authors.lastname: Yin
authors.affiliation: Department of Chemistry, Center for Cell and Genome Science, University of Utah , Salt Lake City, Utah 84112-0850, United States.
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Teuscher
authors.affiliation: Department of Chemistry, Center for Cell and Genome Science, University of Utah , Salt Lake City, Utah 84112-0850, United States.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Chemistry, Center for Cell and Genome Science, University of Utah , Salt Lake City, Utah 84112-0850, United States.
authors.forename: Haitao
authors.initials: H
authors.lastname: Ji
keywords: B-cell lymphoma 9; Wnt signaling; inhibitor; protein−protein interactions; selectivity; β-Catenin