| Description |
Selective disruption of protein-protein interactions by small molecules is important for probing the structure and dynamic aspects of the cellular network. It can also provide new therapeutic targets. β-Catenin of the canonical Wnt signaling pathway uses the same positively charged groove to bind with T-cell factor (Tcf), cadherin, and adenomatous polyposis Coli (APC). The extravagant formation of β-catenin/Tcf interactions drives the initiation and progression of many cancers and fibrosis, while β-catenin/cadherin and β-catenin/APC interactions are essential for cellâ€"cell adhesion and β-catenin degradation. In this study, a selective binding site that can differentiate β-catenin/Tcf, β-catenin/cadherin and β-catenin/APC interactions was identified by alanine scanning and biochemical assays. In Chapter 2, a new peptidomimetic strategy was used to design selective small-molecule inhibitors for β-catenin/Tcf interactions. A potent inhibitor was discovered to bind with β-catenin and completely disrupt β-catenin/Tcf interactions. It also exhibits dual selectivity for β-catenin/Tcf over β-catenin/cadherin and β-catenin/APC interactions in both biochemical and cell-based assays. The study provides a proof of concept for designing selective inhibitors of β-catenin/Tcf interactions. To develop a more drug-like compound, Chapter 3 focused on the modification of the inhibitors discovered in Chapter 2. The replacement of the peptide bond with a benzene ring brought up an interesting off-target outcome. |
