Discovery of Small-Molecule Inhibitors of the PTK7/β-Catenin Interaction Targeting the Wnt Signaling Pathway in...

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Colorectal cancer (CRC) is a leading global cause of cancer death, necessitating novel therapeutic targets.
• Pseudokinase PTK7 plays a role in Wnt/β-catenin signaling and is overexpressed in CRC, correlating with metastasis and reduced survival.
• Aberrant Wnt/β-catenin signaling, due to β-catenin accumulation, is common in CRC.

Purpose of the Study:

• To investigate the PTK7/β-catenin interaction as a potential therapeutic target in CRC.
• To identify small-molecule inhibitors capable of disrupting the PTK7/β-catenin interaction.
• To evaluate the efficacy of these inhibitors in CRC cells.

Main Methods:

• Development of a NanoBRET screening assay to monitor PTK7/β-catenin interaction.
• High-throughput screening (HTS) to identify small-molecule inhibitors.
• In vitro testing of identified inhibitors in CRC cell lines with specific mutations (β-catenin or APC).

Main Results:

• Identification of small-molecule inhibitors that disrupt the PTK7/β-catenin interaction.
• Demonstration of antiproliferative and antitumor effects of these inhibitors in CRC cells.
• Confirmation that targeting the PTK7/β-catenin interaction inhibits Wnt signaling-dependent cell growth.

Conclusions:

• Inhibition of the PTK7/β-catenin interaction represents a novel therapeutic strategy for CRC.
• Targeting PTK7, despite its pseudokinase nature, offers potential for drug development in CRC.
• The identified small molecules show promise for future CRC drug development by targeting Wnt pathway signaling.