| Assay Method Information | |
| | Small-Molecule Inhibitors of the β-Catenin/B-Cell Lymphoma 9 Protein-Protein Interaction |
| Description: | The β-catenin/BCL9 protein-protein interaction (PPI) has emerged as a potential therapeutic target to suppress the hyperactive Wnt/β-catenin signaling that is vigorously involved in tumor initiation and development. Herein, we report the medicinal chemistry optimization on a screening hit to yield a series of novel small-molecule inhibitors of β-catenin/BCL9 PPI. The best compound 30 was found to disrupt the β-catenin/BCL9 PPI with a Ki of 3.6 μM in AlphaScreen competitive inhibition assays. Cell-based studies revealed that 30 selectively disrupted the β-catenin/BCL9 interaction while leaving the β-catenin/E-cadherin complex unaffected, dose-dependently suppressed transactivation of Wnt/β-catenin signaling, downregulated expression of Wnt target genes, and selectively inhibited viability of cancer cells with hyperactive β-catenin signaling. This compound could serve as a lead compound for further optimization of inhibitors of β-catenin/BCL9 PPI. |
| Affinity data for this assay | |
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