Design and synthesis of selective inhibitors for β-catenin/t-cell factor-4 protein-protein interaction

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Title Design and synthesis of selective inhibitors for β-catenin/t-cell factor-4 protein-protein interaction
Publication Type dissertation
School or College College of Science
Department Chemistry
Author Huang, Zheng
Date 2017
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.
Type Text
Publisher University of Utah
Subject beta-catenin; hot spot based design; peptidomimetics; Wnt signaling pathway
Dissertation Name Doctor of Philosophy
Language eng
Rights Management ©Zheng Huang
Format application/pdf
Format Medium application/pdf
ARK ark:/87278/s64f5wbc
Setname ir_etd
ID 1349732
Reference URL https://collections.lib.utah.edu/ark:/87278/s64f5wbc
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