Rational Design and Synthesis of Selective Small-Molecule Inhibitors for Protein–Protein Interactions

Ji will discuss the design of a generic scaffold that itself can mimic the binding mode of hydrophobic side chains of α-helical hot spots at positions i, i + 3, and i + 7 and the application of this generic scaffold to discover selective small-molecule inhibitors for the β-catenin/B-Cell Lymphoma 9 protein-protein interaction (PPI).

Ji will also discuss the design of small-molecule PPI inhibitors using the bioisosteric replacement technique. A binding site in β-catenin that is selective for β-catenin/Tcf over β-catenin/cadherin and β-catenin/adenomatous polyposis coli (APC) PPIs was identified. Potent and selective inhibitors that can target this binding site were designed and synthesized through peptidomimetic strategy and fragment evolution. Biochemical and cell-based studies demonstrated that these small-molecule inhibitors were potent and selective for the β-catenin/Tcf PPI.

These studies aim to address two important questions in the field of drug discovery for PPIs: (1) how to convert hot spot knowledge at PPI interfaces to small-molecule inhibitors; and (2) how to design selective PPI inhibitors.