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J Med Chem. 2015 Jun 11;58(11):4678-92. doi: 10.1021/acs.jmedchem.5b00223. Epub 2015 May 22.

Discovery of Selective Small-Molecule Inhibitors for the β-Catenin/T-Cell Factor Protein-Protein Interaction through the Optimization of the Acyl Hydrazone Moiety.

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Department of Chemistry, Center for Cell and Genome Science, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112-0850, United States.


Acyl hydrazone is an important functional group for the discovery of bioactive small molecules. This functional group is also recognized as a pan assay interference structure. In this study, a new small-molecule inhibitor for the β-catenin/Tcf protein-protein interaction (PPI), ZINC02092166, was identified through AlphaScreen and FP assays. This compound contains an acyl hydrazone group and exhibits higher inhibitory activities in cell-based assays than biochemical assays. Inhibitor optimization resulted in chemically stable derivatives that disrupt the β-catenin/Tcf PPI. The binding mode of new inhibitors was characterized by site-directed mutagenesis and structure-activity relationship studies. This series of inhibitors with a new scaffold exhibits dual selectivity for β-catenin/Tcf over β-catenin/cadherin and β-catenin/APC PPIs. One derivative of this series suppresses canonical Wnt signaling, downregulates the expression of Wnt target genes, and inhibits the growth of cancer cells. This compound represents a solid starting point for the development of potent and selective β-catenin/Tcf inhibitors.

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