Abstract
Concomitant inhibition of key epigenetic pathways involved in silencing tumor suppressor genes has been recognized as a promising strategy for cancer therapy. Herein, we report a first-in-class series of quinoline-based analogues that simultaneously inhibit histone deacetylases (from a low nanomolar range) and DNA methyltransferase-1 (from a mid-nanomolar range, IC50 < 200 nM). Additionally, lysine methyltransferase G9a inhibitory activity is achieved (from a low nanomolar range) by introduction of a key lysine mimic group at the 7-position of the quinoline ring. The corresponding epigenetic functional cellular responses are observed: histone-3 acetylation, DNA hypomethylation, and decreased histone-3 methylation at lysine-9. These chemical probes, multitarget epigenetic inhibitors, were validated against the multiple myeloma cell line MM1.S, demonstrating promising in vitro activity of 12a (CM-444) with GI50 of 32 nM, an adequate therapeutic window (>1 log unit), and a suitable pharmacokinetic profile. In vivo, 12a achieved significant antitumor efficacy in a xenograft mouse model of human multiple myeloma.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Cell Line, Tumor
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Cell Proliferation / drug effects
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DNA (Cytosine-5-)-Methyltransferase 1 / antagonists & inhibitors*
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DNA (Cytosine-5-)-Methyltransferase 1 / metabolism
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Drug Design
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Enzyme Inhibitors / therapeutic use
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Histocompatibility Antigens / metabolism
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Histone Deacetylase Inhibitors / chemistry*
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Histone Deacetylase Inhibitors / pharmacology*
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Histone Deacetylase Inhibitors / therapeutic use
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Histone Deacetylases / metabolism
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Histone-Lysine N-Methyltransferase / antagonists & inhibitors*
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Histone-Lysine N-Methyltransferase / metabolism
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Humans
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Mice
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Mice, Inbred BALB C
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Molecular Docking Simulation
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Neoplasms / drug therapy
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Neoplasms / metabolism
Substances
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Antineoplastic Agents
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Enzyme Inhibitors
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Histocompatibility Antigens
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Histone Deacetylase Inhibitors
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DNA (Cytosine-5-)-Methyltransferase 1
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DNMT1 protein, human
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EHMT2 protein, human
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Histone-Lysine N-Methyltransferase
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Histone Deacetylases