Identification and characterization of a novel small-molecule inhibitor of β-catenin signaling

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Hepatocellular carcinoma (HCC) is a leading cause of cancer death with limited treatment options.
• Wnt/β-catenin signaling pathway activation is common in HCC, presenting a therapeutic target.
• ICG-001, a known Wnt inhibitor, disrupts β-catenin-CREB binding.

Purpose of the Study:

• To identify novel small-molecule inhibitors of Wnt/β-catenin signaling for HCC treatment.
• To characterize the efficacy and specificity of a newly identified compound, PMED-1.

Main Methods:

• Utilized the ZINC database to find compounds structurally similar to ICG-001.
• Assessed PMED-1's effect on β-catenin activity in HCC cell lines using TOPflash reporter assays.
• Evaluated PMED-1's impact on cell proliferation, viability, and Wnt target gene expression.
• Investigated PMED-1's mechanism of action by examining β-catenin-CREB binding and kinase activity.
• Validated PMED-1's efficacy in a zebrafish model of Wnt signaling.

Main Results:

• PMED-1 demonstrated significant inhibition of β-catenin activity in HCC and hepatoblastoma cells (IC50: 4.87–32 μmol/L).
• PMED-1 reduced Wnt target gene expression and impaired HCC cell proliferation and viability without toxicity in primary human hepatocytes.
• The compound specifically decreased β-catenin-CREB binding without affecting other kinases.
• Inhibition of Wnt signaling by PMED-1 was confirmed in vitro and in vivo, with effects lasting 12–24 hours and 6–15 hours, respectively.

Conclusions:

• PMED-1 is a novel, specific small-molecule inhibitor of Wnt/β-catenin signaling identified through computational screening.
• PMED-1 exhibits therapeutic potential for hepatocellular carcinoma by targeting the Wnt pathway.
• This study highlights a cost-effective method for discovering targeted cancer therapies.