Abstract
Chemical manipulations performed on the histone H3 lysine 9 methyltransferases (G9a/GLP) inhibitor BIX-01294 afforded novel desmethoxyquinazolines able to inhibit the DNA methyltransferase DNMT3A at low micromolar levels without any significant inhibition of DNMT1 and G9a. In KG-1 cells such compounds, when tested at sub-toxic doses, induced the luciferase re-expression in a stable construct controlled by a cytomegalovirus (CMV) promoter silenced by methylation (CMV-luc assay). Finally, in human lymphoma U-937 and RAJI cells, the N-(1-benzylpiperidin-4-yl)-2-(4-phenylpiperazin-1-yl)quinazolin-4-amine induced the highest proliferation arrest and cell death induction starting from 10 µM, in agreement with its DNMT3A inhibitory potency.
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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Azepines / chemistry*
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Azepines / metabolism
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Azepines / pharmacology*
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Catalytic Domain
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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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DNA (Cytosine-5-)-Methyltransferases / antagonists & inhibitors*
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DNA (Cytosine-5-)-Methyltransferases / chemistry
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DNA (Cytosine-5-)-Methyltransferases / metabolism
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DNA Methyltransferase 3A
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / metabolism
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Enzyme Inhibitors / pharmacology*
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Histocompatibility Antigens / chemistry
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Histocompatibility Antigens / metabolism
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Histone-Lysine N-Methyltransferase / antagonists & inhibitors*
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Histone-Lysine N-Methyltransferase / chemistry
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Histone-Lysine N-Methyltransferase / metabolism
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Humans
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Molecular Docking Simulation
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Quinazolines / chemistry*
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Quinazolines / metabolism
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Quinazolines / pharmacology*
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Structure-Activity Relationship
Substances
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Azepines
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BIX 01294
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DNMT3A protein, human
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Enzyme Inhibitors
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Histocompatibility Antigens
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Quinazolines
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DNA (Cytosine-5-)-Methyltransferases
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DNA Methyltransferase 3A
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EHMT2 protein, human
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Histone-Lysine N-Methyltransferase