Novel Pyrrolopyrimidine-Based α-Helix Mimetics: Cell- Permeable Inhibitors of Protein-Protein Interactions

Abstract

There is considerable interest in developing nonpeptidic, small molecule α-helix mimetics to disrupt α-helix-mediated protein-protein interactions. Herein, we report the design of a novel pyrrolopyrimidine-based scaffold for such α-helix mimetics with increased conformational rigidity. We also developed a facile solid phase synthetic route, which is amenable to divergent synthesis of a large library. Using a fluorescence polarization-based assay, we identified cell permeable, dual MDMX/MDM2 inhibitors, demonstrating that the designed molecules can act as α-helix mimetics.