Hot Spot-Based Design of Small-Molecule Inhibitors for B-Catenin/T-Cell Factor and B-Catenin/B-Cell Lymphoma 9 Interactions

March 27, 2015

Haitao Ji

In 1995, Clackson and Wells proposed that hot spots at the protein–protein interaction (PPI) interfaces might provide the key for designing PPI inhibitors (Science 1995, 267, 383–386). However, how to achieve a conversion of hot spot knowledge to small-molecule inhibitors is an unsolved task. I will discuss our experience in hot spot-based design of small-molecule inhibitors for β-catenin/T-cell factor (Tcf) and β-catenin/B-Cell Lymphoma 9 (BCL9) PPIs, two key downstream effectors of canonical Wnt signaling. A hot spot pocket in β-catenin that is selective for β-catenin/Tcf over β-catenin/cadherin and β-catenin/adenomatous polyposis coli PPIs were identified. Potent and selective inhibitors specific for the β-catenin/Tcf PPI were discovered through fragment hopping. A new scaffold that can directly mimic the side chains of residues i, i + 3, and i + 7 of an α-helix was also discovered through fragment hopping. Based on this scaffold, new potent inhibitors selective for the β-catenin/BCL9 PPI were designed and synthesized.