Abstract
The MDM2 oncogene has been suggested as a molecular target for treating human cancers, including breast cancer. Most MDM2 inhibitors under development are targeting the MDM2-p53 binding, and have little or no effects on cancers without functional p53, such as advanced breast cancer. The present study was designed to develop a new class of MDM2 inhibitors that exhibit anticancer activity in MDM2-dependent and p53-independent manners. The selective MDM2 inhibitors were discovered by a computational structure-based screening, yielding a lead compound, termed JapA. We further found that JapA inhibited cell growth, decreased cell proliferation, and induced G2/M phase arrest and apoptosis in breast cancer cells through an MDM2-dependent mechanism, regardless of p53 status. It also inhibited the tumor growth and lung metastasis in breast cancer xenograft models without causing any host toxicity. Furthermore, JapA directly bound to MDM2 protein and reduced MDM2 levels in cancer cells in vitro and in vivo by promoting MDM2 protein degradation and inhibiting MDM2 transcription, which is distinct from the existing MDM2 inhibitors. In conclusion, JapA represents a new class of MDM2 inhibitor that exerts its anticancer activity through directly down-regulating MDM2, and might be developed as a novel cancer therapeutic agent.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Validation Study
MeSH terms
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / metabolism
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Binding Sites
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / enzymology
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Breast Neoplasms / genetics
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Breast Neoplasms / pathology
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Cell Proliferation / drug effects
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Dose-Response Relationship, Drug
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Drug Design
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / metabolism
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Enzyme Inhibitors / pharmacology*
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Female
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G2 Phase Cell Cycle Checkpoints / drug effects
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Humans
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Lung Neoplasms / enzymology
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Lung Neoplasms / prevention & control
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Lung Neoplasms / secondary
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MCF-7 Cells
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Mice, Nude
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Models, Molecular
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Molecular Structure
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Molecular Targeted Therapy
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Protein Binding
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Protein Conformation
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Protein Stability
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Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
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Proto-Oncogene Proteins c-mdm2 / chemistry
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Proto-Oncogene Proteins c-mdm2 / genetics
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Proto-Oncogene Proteins c-mdm2 / metabolism
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RNA Interference
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Signal Transduction / drug effects
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Structure-Activity Relationship
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Time Factors
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Transcription, Genetic
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Transfection
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Tumor Burden
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Tumor Suppressor Protein p53 / genetics
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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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Enzyme Inhibitors
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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