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ID: ALA4840323
Journal: J Med Chem
Title: Discovery of an Orally Bioavailable Small-Molecule Inhibitor for the β-Catenin/B-Cell Lymphoma 9 Protein-Protein Interaction.
Authors: Wang Z, Zhang M, Quereda V, Frydman SM, Ming Q, Luca VC, Duckett DR, Ji H.
Abstract: Aberrant activation of Wnt/β-catenin signaling is strongly associated with many diseases including cancer invasion and metastasis. Small-molecule targeting of the central signaling node of this pathway, β-catenin, is a biologically rational approach to abolish hyperactivation of β-catenin signaling but has been demonstrated to be a difficult task. Herein, we report a drug-like small molecule, ZW4864, that binds with β-catenin and selectively disrupts the protein-protein interaction (PPI) between B-cell lymphoma 9 (BCL9) and β-catenin while sparing the β-catenin/E-cadherin PPI. ZW4864 dose-dependently suppresses β-catenin signaling activation, downregulates oncogenic β-catenin target genes, and abrogates invasiveness of β-catenin-dependent cancer cells. More importantly, ZW4864 shows good pharmacokinetic properties and effectively suppresses β-catenin target gene expression in the patient-derived xenograft mouse model. This study offers a selective chemical probe to explore β-catenin-related biology and a drug-like small-molecule β-catenin/BCL9 disruptor for future drug development.
CiteXplore: 34382808