Identification of selective protein-protein interaction inhibitors using efficient peptide-directed ligand design.

The development of protein-protein interaction (PPI) inhibitors with therapeutic value is of increasing importance as the first clinical agent has now been approved, but PPIs remain difficult targets for the development of small molecule ligands. This article describes a highly efficient approach to the development of inhibitors of the p53/DMX or DM2 interaction that involves the design of small molecules based upon a peptide/protein structure. The process for molecule design, starting from a virtual library of just over 1200 fragments, led to the eventual synthesis of twenty compounds, of which ten bound to either DM2, DMX or both in binding assays. This 50% success rate is extremely efficient compared to traditional high throughput screening. The identification of two selective DMX inhibitors from twenty compounds highlights this efficiency as, to date, only two other DMX-selective agents exist in the literature. Preliminary biological studies show that 20% of the compounds identified have cellular activity and activate downstream pathways associated with p53 activation.