Progress in the development of protein-protein interface-specific inhibitors has been slow because of several obstacles, including large seemingly featureless interaction surfaces, discontinuous distribution of �hot spots�, and the adaptability of protein surfaces for protein-protein interactions. To address these challenges, we are developing an innovative new strategy to design small-molecule inhibitors targeting a specific protein-protein interface. The aberrant formation of the �-catenin/Tcf complex in the canonical Wnt/�-catenin signaling cascades has been recognized as the major driving force for human tumorigenesis. Crystallographic analyses, however, show that the essential areas of �-catenin for binding to Tcf, E-cadherin (essential for cell-cell adhesion) and APC (important for �-catenin degradation) are identical. Therefore, the design of small molecules that selectively disrupt the �-catenin/Tcf interactions while leaving the �-catenin/E-cadherin and �-catenin/APC interactions untouched is critical but challenging. By using the new strategy we are developing, we successfully designed and synthesized the potent inhibitors with novel scaffolds.

Novel small-molecule inhibitors for β-catenin/Tcf protein-protein interactions

244th National Meeting (2012)

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