Abstract
A series of N-hydroxy-3-phenyl-2-propenamides were prepared as novel inhibitors of human histone deacetylase (HDAC). These compounds were potent enzyme inhibitors, having IC(50)s < 400 nM in a partially purified enzyme assay. However, potency in cell growth inhibition assays ranged over 2 orders of magnitude in two human carcinoma cell lines. Selected compounds having cellular IC(50) < 750 nM were tested for maximum tolerated dose (MTD) and for efficacy in the HCT116 human colon tumor xenograft assay. Four compounds having an MTD > or = 100 mg/kg were selected for dose-response studies in the HCT116 xenograft model. One compound, 9 (NVP-LAQ824), had significant dose-related activity in the HCT116 colon and A549 lung tumor models, high MTD, and low gross toxicity. On the basis, in part, of these properties, 9 has entered human clinical trials in 2002.
MeSH terms
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Acetyltransferases / antagonists & inhibitors*
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Acrylamides / chemical synthesis*
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Acrylamides / pharmacology*
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacology*
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Body Weight / drug effects
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Cell Division / 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 / pharmacology*
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Female
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Histone Acetyltransferases
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Humans
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Hydroxamic Acids / chemical synthesis*
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Hydroxamic Acids / pharmacology*
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Indicators and Reagents
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Mice
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Mice, Nude
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Molecular Conformation
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Neoplasm Transplantation
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Saccharomyces cerevisiae Proteins / antagonists & inhibitors*
Substances
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Acrylamides
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Antineoplastic Agents
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Enzyme Inhibitors
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Hydroxamic Acids
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Indicators and Reagents
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Saccharomyces cerevisiae Proteins
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Acetyltransferases
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Histone Acetyltransferases