Structure-Based Design of Potent and Orally Active Isoindolinone Inhibitors of MDM2-p53 Protein-Protein Interaction.
Gianni ChessariIan R HardcastleJong Sook AhnBurcu AnilElizabeth AnscombeRuth H BawnLuke D BevanTimothy J BlackburnIldiko BuckCeline CanoBenoit CarbainJuan CastroBen ConsSarah J CullyJane A EndicottLynsey FazalBernard T GoldingRoger J GriffinKaren HaggertySuzannah J HarnorKeisha HearnStephen HobsonRhian S HolveySteven HowardClaire E JenningsChristopher N JohnsonJohn LunecDuncan C MillerDavid R NewellMartin E M NobleJudith ReeksCharlotte H RevillChristiane RiedingerJeffrey D St DenisEmiliano TamaniniHuw ThomasNeil T ThompsonMladen VinkovićStephen R WedgePamela A WilliamsNicola E WilsherBian ZhangYan ZhaoPublished in: Journal of medicinal chemistry (2021)
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.