Structure-Based Design of 1,4-Dibenzoylpiperazines as β-Catenin/B-Cell Lymphoma 9 Protein-Protein Interaction Inhibitors

A small-molecule inhibitor with a 1,4-dibenzoylpiperazine scaffold was designed to match the critical binding elements in the beta-catenin/B-cell lymphoma 9 (BCL9) protein protein interaction interface. Inhibitor optimization led to a potent inhibitor that can disrupt the beta-catenin/BCL9 interaction and exhibit 98-fold selectivity over the beta-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/beta-catenin-dependent cancer cells.