Target β-catenin/CD44/Nanog axis in colon cancer cells by certain N'-(2-oxoindolin-3-ylidene)-2-(benzyloxy)benzohydrazides

Area of Science:

• Medicinal Chemistry
• Cancer Biology
• Molecular Pharmacology

Background:

• The cell surface molecule CD44 is crucial for regulating cancer stem cells (CSCs) phenotypically and functionally.
• Targeting CSCs via chemical inhibition of CD44 remains an underexplored therapeutic strategy.

Purpose of the Study:

• To discover novel chemical inhibitors targeting CD44 for potential CSC eradication.
• To elucidate the mechanism of action of these novel inhibitors.
• To evaluate the targeted effects on CSC-related transcriptional factors.

Main Methods:

• Synthesis and characterization of novel N'-(2-oxoindolin-3-ylidene)-2-(benzyloxy)benzohydrazide derivatives.
• Molecular docking studies to predict binding interactions with the β-catenin/TCF-4 complex.
• Assays for TCF/LEF reporter activity, Nanog, Sox2, and Oct-4 expression.
• Cytotoxicity and cell cycle analysis correlated with CD44 expression.

Main Results:

• Discovery of N'-(2-oxoindolin-3-ylidene)-2-(benzyloxy)benzohydrazides as potent CD44 inhibitors.
• Molecular docking revealed interference with the β-catenin/TCF-4 complex, linking CD44 inhibition to Wnt pathway modulation.
• Compound 11a inhibited TCF/LEF reporter activity and Nanog expression, indicating Wnt pathway and specific transcriptional factor inhibition.
• Cytotoxicity and cell cycle effects were observed to be dependent on CD44 expression levels.

Conclusions:

• Novel benzohydrazide derivatives effectively inhibit CD44 and target cancer stem cells.
• The mechanism involves Wnt pathway inhibition and specific downregulation of Nanog.
• These findings highlight a promising therapeutic strategy for CD44-expressing cancers.