Abstract Colorectal cancer (CRC) is one of the most common gastrointestinal malignancies. The development of novel targeted drug therapeutics against CRC has been a research hotspot. Among these strategies, disrupting the β-catenin/BCL9 protein–protein interaction (PPI) emerges as a promising approach for the treatment of CRC driven by aberrant Wnt signaling. Currently, most β-catenin/BCL9 PPI inhibitors are peptide-based; however, their intrinsic limitations have hindered further development. Among small-molecule inhibitors, phenylpiperidine derivatives have progressed rapidly. In this study, based on the phenylpiperidine scaffold, we designed and synthesized a series of compounds (A1–A20). Their activities as β-catenin/BCL9 PPI inhibitors were preliminarily evaluated through antiproliferative assays on CRC cells and competitive fluorescence polarization assays. Among these compounds, methyl 2-(4-((4'-isopropyl-1,1'-biphenyl-4-carboxamido)methyl)phenoxy)-2-methylpropanoate (A3) showed selective inhibition of the proliferation of Wnt-dependent CRC cells and showed the inhibitory potency against the β-catenin/BCL9 interaction. Molecular docking confirmed that A3 fits well into the β-catenin binding pocket, forming key interactions consistent with the lead compound. These results identify A3 as a promising lead for anti-CRC activity.
Long et al. (Thu,) studied this question.
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