Abstract
For the early diagnosis of cancer, leading to a better chance of full recovery, marker genes whose expression is already altered in precancerous lesions are desirable, and the tumor-suppressor gene FHIT is one candidate. The gene product, FHIT protein, has a unique dinucleoside triphosphate hydrolase (AP3Aase) activity, and in this study, we designed and synthesized a series of FHIT fluorescent probes utilizing this activity. We optimized the probe structure for high and specific reactivity with FHIT and applied the optimized probe in a screening assay for FHIT inhibitors. Screening of a compound library with this assay identified several hits. Structural development of a hit compound afforded potent FHIT inhibitors. These inhibitors induce apoptosis in FHIT-expressing cancers via caspase activation. Our results support the idea that FHIT binders, no matter whether inhibitors or agonists of AP3Aase activity, might be promising anticancer agents.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acid Anhydride Hydrolases / antagonists & inhibitors*
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Acid Anhydride Hydrolases / genetics
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Acid Anhydride Hydrolases / metabolism
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Antineoplastic Agents / chemical synthesis
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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 Line, Tumor
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Dose-Response Relationship, Drug
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Drug Design*
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Drug Screening Assays, Antitumor
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Fluorescent Dyes / chemical synthesis
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Fluorescent Dyes / chemistry
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Fluorescent Dyes / pharmacology*
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Humans
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Molecular Structure
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Enzyme Inhibitors
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Fluorescent Dyes
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Neoplasm Proteins
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fragile histidine triad protein
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Acid Anhydride Hydrolases