Abstract
p53-Murine double minute 2 (MDM2) interaction and histone deacetylases (HDACs) are important targets in antitumor drug development. Inspired by the synergistic effects between MDM2 and HDACs, the first MDM2/HDACs dual inhibitors were identified, which showed excellent activities against both targets. In particular, compound 14d was proven to be a potent and orally active MDM2/HDAC dual inhibitor, whose antitumor mechanisms were validated in cancer cells. Compound 14d showed excellent in vivo antitumor potency in the A549 xenograft model, providing a promising lead compound for the development of novel antitumor agents. Also, this proof-of-concept study offers a novel and efficient strategy for multitargeting antitumor drug discovery.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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A549 Cells
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Acetylation / drug effects
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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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Binding Sites
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Drug Design
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Female
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Histone Deacetylase Inhibitors / chemistry
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Histone Deacetylase Inhibitors / pharmacology*
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Histone Deacetylases / metabolism
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Histones / metabolism
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Humans
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Mice, Nude
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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, Sprague-Dawley
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Small Molecule Libraries / pharmacology
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Stereoisomerism
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Structure-Activity Relationship
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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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Histone Deacetylase Inhibitors
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Histones
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Small Molecule Libraries
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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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Mdm2 protein, mouse
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Proto-Oncogene Proteins c-mdm2
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Histone Deacetylases