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Structure-Based Optimization of Small-Molecule Inhibitors for the ?-Catenin/B-Cell Lymphoma 9 Protein-Protein Interaction.

ABSTRACT: Structure-based optimization was conducted to improve the potency, selectivity, and cell-based activities of ?-catenin/B-cell lymphoma 9 (BCL9) inhibitors based on the 4'-fluoro- N-phenyl-[1,1'-biphenyl]-3-carboxamide scaffold, which was designed to mimic the side chains of the hydrophobic ?-helical hot spots at positions i, i + 3, and i + 7. Compound 29 was found to disrupt the ?-catenin/BCL9 protein-protein interaction (PPI) with a Ki of 0.47 ?M and >1900-fold selectivity for ?-catenin/BCL9 over ?-catenin/E-cadherin PPIs. The proposed binding mode of new inhibitors was consistent with the results of site-directed mutagenesis and structure-activity relationship studies. Cell-based studies indicated that 29 disrupted the ?-catenin/BCL9 interaction without affecting the ?-catenin/E-cadherin interaction, selectively suppressed transactivation of Wnt/?-catenin signaling, downregulated expression of Wnt target genes, and inhibited viability of Wnt/?-catenin-dependent cancer cells in dose-dependent manners. A comparison of the biochemical and cell-based assay results offered the directions for future inhibitor optimization.

SUBMITTER: Zhang M 

PROVIDER: S-EPMC7787347 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Structure-Based Optimization of Small-Molecule Inhibitors for the β-Catenin/B-Cell Lymphoma 9 Protein-Protein Interaction.

Zhang Min M   Wang Zhen Z   Zhang Yongqiang Y   Guo Wenxing W   Ji Haitao H  

Journal of medicinal chemistry 20180329 7

Structure-based optimization was conducted to improve the potency, selectivity, and cell-based activities of β-catenin/B-cell lymphoma 9 (BCL9) inhibitors based on the 4'-fluoro- N-phenyl-[1,1'-biphenyl]-3-carboxamide scaffold, which was designed to mimic the side chains of the hydrophobic α-helical hot spots at positions i, i + 3, and i + 7. Compound 29 was found to disrupt the β-catenin/BCL9 protein-protein interaction (PPI) with a K<sub>i</sub> of 0.47 μM and >1900-fold selectivity for β-cate  ...[more]

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