Discovery of an Orally Bioavailable Small-Molecule Inhibitor for the β‑Catenin/B-Cell Lymphoma 9 Protein–Protein Interaction

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.