Abstract
We have designed MI-219 as a potent, highly selective and orally active small-molecule inhibitor of the MDM2-p53 interaction. MI-219 binds to human MDM2 with a K(i) value of 5 nM and is 10,000-fold selective for MDM2 over MDMX. It disrupts the MDM2-p53 interaction and activates the p53 pathway in cells with wild-type p53, which leads to induction of cell cycle arrest in all cells and selective apoptosis in tumor cells. MI-219 stimulates rapid but transient p53 activation in established tumor xenograft tissues, resulting in inhibition of cell proliferation, induction of apoptosis, and complete tumor growth inhibition. MI-219 activates p53 in normal tissues with minimal p53 accumulation and is not toxic to animals. MI-219 warrants clinical investigation as a new agent for cancer treatment.
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 / administration & dosage
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Antineoplastic Agents / blood
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects*
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Cell Cycle / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Humans
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Indoles / administration & dosage
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Indoles / blood
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Indoles / chemistry
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Indoles / pharmacology*
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Mice
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Models, Molecular
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Neoplasms / pathology*
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Protein Binding / drug effects
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Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
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Spiro Compounds / administration & dosage
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Spiro Compounds / blood
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Spiro Compounds / chemistry
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Spiro Compounds / pharmacology*
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Time Factors
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Tumor Suppressor Protein p53 / metabolism*
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Indoles
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MI-219
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Spiro Compounds
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Tumor Suppressor Protein p53
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2