Abstract
Selective inhibitors of human peptide deformylase (HsPDF) are predicted to constitute a new class of antitumor agents. We report the identification of benzofuran-4,5-diones as the first known selective HsPDF inhibitors and we describe their selectivity profile in a panel of metalloproteases. We characterize their structure-activity relationships for antitumor activity in a panel of cancer cell lines, and we assess their in vivo efficacy in a mouse xenograft model. Our results demonstrate that selective HsPDF inhibitors based on the benzofuran-4,5-dione scaffold constitute a novel class of antitumor agents that are potent in vitro and in vivo.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amidohydrolases / antagonists & inhibitors*
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Amidohydrolases / metabolism
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Animals
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / therapeutic use
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Antineoplastic Agents / toxicity
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Benzofurans / chemistry*
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Benzofurans / therapeutic use
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Benzofurans / toxicity
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Cell Line, Tumor
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Drug Screening Assays, Antitumor
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / therapeutic use
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Enzyme Inhibitors / toxicity
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Humans
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Hydroxamic Acids / chemistry
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Metalloproteases / antagonists & inhibitors
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Metalloproteases / metabolism
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Mice
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Mice, Nude
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Neoplasms / drug therapy
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Structure-Activity Relationship
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Transplantation, Heterologous
Substances
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Antineoplastic Agents
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Benzofurans
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Enzyme Inhibitors
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Hydroxamic Acids
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Metalloproteases
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Amidohydrolases
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peptide deformylase
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benzofuran