title: Rational design of small-molecule inhibitors for β-catenin/T-cell factor protein-protein interactions by bioisostere replacement.
abstract: A new hot spot-based design strategy using bioisostere replacement is reported to rationally design nonpeptidic small-molecule inhibitors for protein-protein interactions. This method is applied to design new potent inhibitors for β-catenin/T-cell factor (Tcf) interactions. Three hot spot regions of Tcf for binding to β-catenin were quantitatively evaluated; the key binding elements around K435 and K508 of β-catenin were derived; a bioisostere library was used to generate new fragments that can match the proposed critical binding elements. The most potent inhibitor, with a molecular weight of 230, has a Kd of 0.531 μM for binding to β-catenin and a Ki of 3.14 μM to completely disrupt β-catenin/Tcf interactions. The binding mode of the designed inhibitors was validated by the site-directed mutagenesis and structure-activity relationship (SAR) studies. This study provides a new approach to design new small-molecule inhibitors that bind to β-catenin and effectively disrupt β-catenin/Tcf interactions specific for canonical Wnt signaling.
authors.affiliation: Department of Chemistry, Center for Cell and Genome Science, University of Utah, Salt Lake City, UT 84112-0850, USA.
authors.forename: Binxun
authors.initials: B
authors.lastname: Yu
authors.forename: Zheng
authors.initials: Z
authors.lastname: Huang
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Darren R
authors.initials: DR
authors.lastname: Dillard
authors.forename: Haitao
authors.initials: H
authors.lastname: Ji
mesh_terms: D015195:Drug Design; D005454:Fluorescence Polarization; D008958:Models, Molecular; D015394:Molecular Structure; D008970:Molecular Weight; D011485:Protein Binding / Q000187:drug effects; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D051820:TCF Transcription Factors / Q000037:antagonists & inhibitors*; D051176:beta Catenin / Q000037:antagonists & inhibitors*
chemical_list: D054852:Small Molecule Libraries; D051820:TCF Transcription Factors; D051176:beta Catenin