Abstract
Reactivation of mutant p53 is likely to provide important benefits for treatment of chemotherapy- and radiotherapy-resistant tumors. We demonstrate here that the maleimide-derived molecule MIRA-1 can reactivate DNA binding and preserve the active conformation of mutant p53 protein in vitro and restore transcriptional transactivation to mutant p53 in living cells. MIRA-1 induced mutant p53-dependent cell death in different human tumor cells carrying tetracycline-regulated mutant p53. The structural analog MIRA-3 showed antitumor activity in vivo against human mutant p53-carrying tumor xenografts in SCID mice. The MIRA scaffold is a novel lead for the development of anticancer drugs specifically targeting mutant p53.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology
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Cell Line, Tumor
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Cell Separation
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DNA / chemistry
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Dose-Response Relationship, Drug
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Enzyme-Linked Immunosorbent Assay
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Flow Cytometry
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Glutathione Transferase / metabolism
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Humans
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Maleimides / pharmacology*
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Mice
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Mice, SCID
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Microscopy, Fluorescence
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Models, Chemical
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Mutation
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Neoplasm Transplantation
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Neoplasms / drug therapy*
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Neoplasms / genetics*
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Plasmids / metabolism
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Protein Binding
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Protein Conformation
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Tetracycline / metabolism
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Transcriptional Activation
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Tumor Suppressor Protein p53 / genetics*
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Tumor Suppressor Protein p53 / metabolism
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Tumor Suppressor Protein p53 / physiology*
Substances
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Antineoplastic Agents
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Maleimides
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Tumor Suppressor Protein p53
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maleimide
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DNA
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Glutathione Transferase
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Tetracycline