Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition.
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.
Mesh Terms:
Administration, Oral, Animals, Antineoplastic Agents, Apoptosis, Cell Cycle, Cell Line, Tumor, Cell Proliferation, Humans, Indoles, Mice, Models, Molecular, Neoplasms, Protein Binding, Proto-Oncogene Proteins c-mdm2, Spiro Compounds, Time Factors, Tumor Suppressor Protein p53, Xenograft Model Antitumor Assays
Administration, Oral, Animals, Antineoplastic Agents, Apoptosis, Cell Cycle, Cell Line, Tumor, Cell Proliferation, Humans, Indoles, Mice, Models, Molecular, Neoplasms, Protein Binding, Proto-Oncogene Proteins c-mdm2, Spiro Compounds, Time Factors, Tumor Suppressor Protein p53, Xenograft Model Antitumor Assays
Proc. Natl. Acad. Sci. U.S.A.
Date: Mar. 11, 2008
PubMed ID: 18316739
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