Abstract
Structural analysis of both the MDM2-p53 protein-protein interaction and several small molecules bound to MDM2 led to the design and synthesis of tetrasubstituted morpholinone 10, an MDM2 inhibitor with a biochemical IC50 of 1.0 μM. The cocrystal structure of 10 with MDM2 inspired two independent optimization strategies and resulted in the discovery of morpholinones 16 and 27 possessing distinct binding modes. Both analogues were potent MDM2 inhibitors in biochemical and cellular assays, and morpholinone 27 (IC50 = 0.10 μM) also displayed suitable PK profile for in vivo animal experiments. A pharmacodynamic (PD) experiment in mice implanted with human SJSA-1 tumors showed p21(WAF1) mRNA induction (2.7-fold over vehicle) upon oral dosing of 27 at 300 mg/kg.
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacology*
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Circular Dichroism
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Crystallography
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Crystallography, X-Ray
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Drug Design
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Female
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Humans
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Indicators and Reagents
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Mice
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Mice, Nude
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Models, Molecular
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Morpholines / chemical synthesis
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Morpholines / pharmacology
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Piperidines / chemical synthesis
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Piperidines / pharmacology
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Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
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Stereoisomerism
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Structure-Activity Relationship
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Tumor Suppressor Protein p53 / antagonists & inhibitors*
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Indicators and Reagents
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Morpholines
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Piperidines
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Tumor Suppressor Protein p53
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2
Associated data
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PDB/4JV7
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PDB/4JV9,
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PDB/4JVE
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PDB/4JVR
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PDB/4JWR