Design and Synthesis of Novel β-catenin/BCL9 Protein–Protein Interaction Small Molecule Inhibitors for the Treatment of Colorectal Cancer

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.