A series of 1-(3-(2-amino-2-oxoethoxy)phenyl)piperidine-3-carboxamide derivatives was reported as new small-molecule β-catenin/B-cell lymphoma 9 (BCL9) protein-protein interaction (PPI) inhibitors. Compounds 17-21 were discovered to inhibit the β-catenin/BCL9 PPI with K i = 0.85-2.7 μM. The effects of 21 on the β-catenin/BCL9 PPI in cellular context were demonstrated by β-catenin/BCL9 pull-down inhibition and dose-dependent suppression of Wnt/β-catenin signal transactivation. Notably, compound 21 is more potent than ZW4864, a previously reported analogue, in modulating transcription and expression of β-catenin target genes and suppressing survival of β-catenin-dependent cancer cells. The cellular on-target efficacy of 21 was demonstrated by β-catenin rescue experiments. Compound 21 represents a promising starting point for further optimization of β-catenin/BCL9 PPI inhibitors.
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