Protein�protein interactions (PPIs) play an essential role in most biological processes. It has been estimated that at least 130,000 binary PPIs regulate human life. Proteins tend to use the same interface to interact with the other proteins in different organelles and cellular environments. Under pathological conditions, PPIs lose compartmental constraint and unexpected PPIs take place, which leads to disease. One challenge of biomedical research is to design a drug-like small molecule to selectively disrupt one protein�protein interface while leaving the other related PPIs unaffected. Our lab has been focusing on developing new chemistry tools to rationally design selective PPI inhibitors. The first set of protein-protein complexes we have been working on is �-catenin/T-cell factor (Tcf) PPIs, �-catenin/cadherin PPIs, and �-catenin/adenomatous polysis coli (APC) PPIs. The aberrant formation of the �-catenin/Tcf complex in the downstream site of the canonical Wnt signaling pathway promotes cancer stem cell self-renewal and maintain cancer stem cell resistance to current anti-cancer therapies. On the contrary, the �-catenin/cadherin PPI is essential for the integrity of epithelial junctions, while the �-catenin/cadherin PPI is critical for the degradation of �-catenin in normal cells. Our lab has discovered highly potent and selective �-catenin/Tcf inhibitors using the new techniques recently developed in our lab. We have been validating the binding modes of new selective �-catenin/Tcf inhibitors through site-directed mutagenesis and cell-based studies.

Selective inhibition of �-Catenin/T-cell factor protein-protein interactions by small molecules

247th National Meeting (2014)

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