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 of novel isoindolinone-based MDM2 inhibitors. MDM2 X-ray crystallography,
quantum mechanics ligand-based design, and metabolite identification
all contributed toward the discovery of potent in vitro and in vivo inhibitors of the MDM2-p53 interaction
with representative compounds inducing cytostasis in an SJSA-1 osteosarcoma
xenograft model following once-daily oral administration.