Abstract
We designed and synthesized quinazolin-2,4-dione-based hydroxamic acids to serve as selective competitive inhibitors of histone deacetylase-6 (HDAC6). The most potent and selective compound, 3d (IC50, 4 nM, HDAC6; IC50 > 10 μM, HDAC1), substantially increased acetylation of α-tubulin instead of histones in the lung cancer cell line, LL2. Paclitaxel in combination with 3d had a synergistic anticancer effect on reduction of programmed death-ligand 1 expression in LL/2 cells. When given orally, 3d was mainly found to locate in the liver and lungs, at a concentration 18- to 70-fold greater, respectively, than in plasma. As an orally active HDAC6 inhibitor, 3d (20 mg/kg) potentiated paclitaxel antitumor activity (percentage tumor growth inhibition, 67.5%) in a xenograft syngeneic non-small cell lung cancer mouse model.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation / drug effects
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Animals
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Apoptosis / drug effects*
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B7-H1 Antigen / genetics
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B7-H1 Antigen / metabolism
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Carcinoma, Non-Small-Cell Lung / drug therapy
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Carcinoma, Non-Small-Cell Lung / metabolism
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Carcinoma, Non-Small-Cell Lung / pathology
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Cell Line, Tumor
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Drug Synergism
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Histone Deacetylase 6 / antagonists & inhibitors*
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Histone Deacetylase 6 / metabolism
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Histone Deacetylase Inhibitors / chemistry*
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Histone Deacetylase Inhibitors / metabolism
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Histone Deacetylase Inhibitors / pharmacology
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Histone Deacetylase Inhibitors / therapeutic use
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Humans
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Hydroxamic Acids / chemistry*
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Hydroxamic Acids / metabolism
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Hydroxamic Acids / pharmacology
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Hydroxamic Acids / therapeutic use
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Lung Neoplasms / drug therapy
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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Mice
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Mice, Inbred C57BL
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Paclitaxel / pharmacology
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Quinazolinones / chemistry*
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Structure-Activity Relationship
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Tissue Distribution
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Transplantation, Homologous
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Tubulin / metabolism
Substances
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B7-H1 Antigen
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Histone Deacetylase Inhibitors
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Hydroxamic Acids
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Quinazolinones
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Tubulin
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Histone Deacetylase 6
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Paclitaxel