title: Discovery of Selective Small-Molecule Inhibitors for the β-Catenin/T-Cell Factor Protein-Protein Interaction through the Optimization of the Acyl Hydrazone Moiety.
abstract: 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.
authors.affiliation: Department of Chemistry, Center for Cell and Genome Science, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112-0850, United States.
authors.forename: J Leon
authors.initials: JL
authors.lastname: Catrow
authors.affiliation: Department of Chemistry, Center for Cell and Genome Science, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112-0850, United States.
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Chemistry, Center for Cell and Genome Science, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112-0850, United States.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Chemistry, Center for Cell and Genome Science, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112-0850, United States.
authors.forename: Haitao
authors.initials: H
authors.lastname: Ji
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D055808:Drug Discovery; D004797:Enzyme-Linked Immunosorbent Assay; D057809:HEK293 Cells; D006801:Humans; D006835:Hydrazones / Q000737:chemistry*; D047468:Immunoprecipitation; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D011485:Protein Binding; D060066:Protein Interaction Maps / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D051820:TCF Transcription Factors / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D006835:Hydrazones; D012333:RNA, Messenger; D054852:Small Molecule Libraries; D051820:TCF Transcription Factors; D051176:beta Catenin