Discovery Of An Orally Bioavailable Small-Molecule Inhibitor For The Beta-Catenin/B-Cell Lymphoma 9 Protein-Protein Interaction

Aberrant activation of Wnt/beta-catenin signaling is strongly associated with many diseases including cancer invasion and metastasis. Small-molecule targeting of the central signaling node of this pathway, beta-catenin, is a biologically rational approach to abolish hyperactivation of beta-catenin signaling but has been demonstrated to be a difficult task. Herein, we report a drug-like small molecule, ZW4864, that binds with beta-catenin and selectively disrupts the protein-protein interaction (PPI) between B-cell lymphoma 9 (BCL9) and beta-catenin while sparing the beta-catenin/E-cadherin PPI. ZW4864 dose-dependently suppresses beta-catenin signaling activation, downregulates oncogenic beta-catenin target genes, and abrogates invasiveness of beta-catenin-dependent cancer cells. More importantly, ZW4864 shows good pharmacokinetic properties and effectively suppresses beta-catenin target gene expression in the patient-derived xenograft mouse model. This study offers a selective chemical probe to explore beta-catenin-related biology and a drug-like small-molecule beta-catenin/BCL9 disruptor for future drug development.