Abstract
We report herein the design of potent and orally active small-molecule inhibitors of the MDM2-p53 interaction. Compound 5 binds to MDM2 with a K(i) of 0.6 nM, activates p53 at concentrations as low as 40 nM, and potently and selectively inhibits cell growth in tumor cells with wild-type p53 over tumor cells with mutated/deleted p53. Compound 5 has a good oral bioavailability and effectively inhibits tumor growth in the SJSA-1 xenograft model.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Animals
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology*
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Biological Availability
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Bone Neoplasms / drug therapy
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Bone Neoplasms / metabolism
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Cell Line, Tumor
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Drug Design
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HCT116 Cells
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Humans
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Indoles / chemistry*
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Indoles / pharmacokinetics
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Indoles / pharmacology*
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Mice
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Morpholines / chemistry
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Morpholines / pharmacokinetics
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Morpholines / pharmacology
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Osteosarcoma / drug therapy
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Osteosarcoma / metabolism
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Piperazines / chemistry
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Piperazines / pharmacokinetics
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Piperazines / pharmacology
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Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
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Proto-Oncogene Proteins c-mdm2 / metabolism
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Rats
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Spiro Compounds / chemistry*
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Spiro Compounds / pharmacokinetics
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Spiro Compounds / pharmacology*
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Structure-Activity Relationship
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Tumor Suppressor Protein p53 / antagonists & inhibitors*
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Tumor Suppressor Protein p53 / metabolism
Substances
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Antineoplastic Agents
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Indoles
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MI-63 compound
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Morpholines
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Piperazines
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Spiro Compounds
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TP53 protein, human
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Tumor Suppressor Protein p53
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2