Structure-Based Design of Potent and Orally Active Isoindolinone Inhibitors of MDM2-p53 Protein–Protein Interaction

Inhibition of murine double minute 2 (MDM2)-p53 protein-protein interaction with small molecules has been shown to reactivate p53 and inhibit tumor growth. Here, we describe rational, structure-guided, design novel isoindolinone-based MDM2 inhibitors. X-ray crystallography, quantum mechanics ligand-based design, metabolite identification all contributed toward the discovery potent in vitro vivo inhibitors MDM2-p53 representative compounds inducing cytostasis an SJSA-1 osteosarcoma xenograft model following once-daily oral administration.