Structure-Based Design of Potent and Orally Active Isoindolinone Inhibitors of MDM2-p53 Protein-Protein Interaction.
J Med Chem
; 64(7): 4071-4088, 2021 04 08.
Article
em En
| MEDLINE
| ID: mdl-33761253
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Osteossarcoma
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Proteína Supressora de Tumor p53
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Proteínas Proto-Oncogênicas c-mdm2
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Isoindóis
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Multimerização Proteica
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Antineoplásicos
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article