We report new small molecule β-catenin/B-cell lymphoma 9 (BCL9) protein–protein interaction (PPI) inhibitors with a 1-(3-(2-amino-2-oxoethoxy) phenyl) piperidine-3-carboxamide scaffold. These compounds were designed on the basis of a previously reported inhibitor ZW4864 with the goal of improving activity in cellular contexts. Optimization on the piperidine, dimethyl, cyclopropyl, and pyrazole groups in ZW4864 revealed that only variations on the pyrazole group yielded compounds with comparable activities. Compound 21 in Figure 1 was found to disrupt the β-catenin/BCL9 PPI with an IC50 of 3.4 µM in AlphaScreen competitive inhibition assays. The disruption effects of 21 on the β-catenin/BCL9 PPI in cellular context were demonstrated by β-catenin/BCL9 pull-down inhibition experiments using SW480 cell lysates. Cell-based studies including luciferase reporter, MTS cell proliferation, quantitative PCR, and western blots with unaltered cell lysates revealed that 21 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. Notably, compound 21 is more potent than ZW4864 in suppressing transcription and expression of Wnt target genes and Wnt-dependent cancer cell survival. This compound represents a promising starting point for further optimization of β-catenin/BCL9 PPI inhibitors and characterization of β-catenin mediated protein-protein interactions.

New 1-(3-(2-amino-2-oxoethoxy) phenyl) piperidine-3-carboxamide derivatives as small-molecule inhibitors for the β-catenin/BCL9 protein–protein interaction

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