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

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2021 Aug 12

PMID 34382808

Citations 4

Authors

Zhen Wang

Min Zhang

Victor Quereda

Sylvia M Frydman

Qianqian Ming

Vincent C Luca

Derek R Duckett

Haitao Ji

Affiliations

Soon will be listed here.

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, , 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. dose-dependently suppresses β-catenin signaling activation, downregulates oncogenic β-catenin target genes, and abrogates invasiveness of β-catenin-dependent cancer cells. More importantly, 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.

Citing Articles

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New ZW4864 Derivatives as Small-Molecule Inhibitors for the β-Catenin/BCL9 Protein-Protein Interaction.

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