1. Structure-Based Design of Potent and Orally Active Isoindolinone Inhibitors of MDM2-p53 Protein-Protein Interaction.
- Author
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Chessari G, Hardcastle IR, Ahn JS, Anil B, Anscombe E, Bawn RH, Bevan LD, Blackburn TJ, Buck I, Cano C, Carbain B, Castro J, Cons B, Cully SJ, Endicott JA, Fazal L, Golding BT, Griffin RJ, Haggerty K, Harnor SJ, Hearn K, Hobson S, Holvey RS, Howard S, Jennings CE, Johnson CN, Lunec J, Miller DC, Newell DR, Noble MEM, Reeks J, Revill CH, Riedinger C, St Denis JD, Tamanini E, Thomas H, Thompson NT, Vinković M, Wedge SR, Williams PA, Wilsher NE, Zhang B, and Zhao Y
- Subjects
- Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents metabolism, Bone Neoplasms drug therapy, Cell Line, Tumor, Cell Proliferation drug effects, Crystallography, X-Ray, Drug Stability, Female, Humans, Isoindoles chemical synthesis, Isoindoles metabolism, Macaca fascicularis, Male, Mice, Inbred BALB C, Mice, Nude, Microsomes, Liver metabolism, Molecular Structure, Protein Binding, Structure-Activity Relationship, Xenograft Model Antitumor Assays, Mice, Antineoplastic Agents pharmacology, Isoindoles pharmacology, Osteosarcoma drug therapy, Protein Multimerization drug effects, Proto-Oncogene Proteins c-mdm2 metabolism, Tumor Suppressor Protein p53 metabolism
- Abstract
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.
- Published
- 2021
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