Discovery Of 2-(3-(3-Carbamoylpiperidin-1-Yl)Phenoxy)Acetic Acid Derivatives As Novel Small-Molecule Inhibitors Of The Beta-Catenin/B-Cell Lymphoma 9 Protein-Protein Interaction

The beta-catenin/B-cell lymphoma 9 (BCL9) protein-protein interaction (PPI) is a potential target for the suppression of hyperactive Wnt/beta-catenin signaling that is vigorously involved in cancer initiation and development. Herein, we describe the medicinal chemistry optimization of a screening hit to yield novel small-molecule inhibitors of the beta-catenin/BCL9 interaction. The best compound 30 can disrupt the beta-catenin/BCL9 interaction with a K-i of 3.6 mu M in AlphaScreen competitive inhibition assays. Cell-based experiments revealed that 30 selectively disrupted the beta-catenin/BCL9 PPI, while leaving the beta-catenin/E-cadherin PPI unaffected, dose-dependently suppressed Wnt signaling transactivation, downregulated oncogenic Wnt target gene expression, and on-target selectively inhibited the growth of cancer cells harboring aberrant Wnt signaling. This compound with a new chemotype can serve as a lead compound for further optimization of inhibitors for beta-catenin/BCL9 PPI.