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

Zhen Wang1, Min Zhang1, Victor Quereda1

  • 1Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612-9497, United States.

Journal of Medicinal Chemistry
|August 12, 2021
PubMed

Insights

A new drug, ZW4864, targets the Wnt/β-catenin pathway by disrupting the β-catenin/BCL9 interaction. This approach suppresses cancer cell invasion and shows promise for future drug development.

Area of Science:

  • Molecular Biology
  • Oncology
  • Drug Discovery

Background:

  • Aberrant Wnt/β-catenin signaling drives cancer invasion and metastasis.
  • Targeting β-catenin is a rational strategy, but challenging.
  • Selective disruption of protein-protein interactions (PPIs) is an emerging therapeutic approach.

Purpose of the Study:

  • To identify and characterize a small molecule that selectively inhibits the Wnt/β-catenin pathway.
  • To develop a chemical probe for studying β-catenin biology.
  • To provide a potential therapeutic agent for β-catenin-dependent cancers.

Main Methods:

  • Small molecule screening and characterization.
  • In vitro assays to assess β-catenin signaling inhibition and PPI disruption.
  • In vivo studies using patient-derived xenograft mouse models.
  • Pharmacokinetic profiling.

Main Results:

  • ZW4864 selectively disrupts the β-catenin/BCL9 PPI while sparing the β-catenin/E-cadherin PPI.
  • ZW4864 dose-dependently inhibits Wnt/β-catenin signaling and oncogenic gene expression.
  • ZW4864 abrogates invasiveness of cancer cells and suppresses tumor growth in vivo.
  • ZW4864 exhibits favorable pharmacokinetic properties.

Conclusions:

  • ZW4864 is a potent and selective small-molecule inhibitor of the β-catenin/BCL9 interaction.
  • This compound effectively suppresses Wnt/β-catenin signaling and cancer cell invasiveness.
  • ZW4864 represents a promising drug-like lead for developing novel cancer therapeutics targeting the Wnt pathway.

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