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Novel anticancer drug curaxin CBL0137 impairs DNA methylation by eukaryotic DNA methyltransferase Dnmt3a
Institution:1. Department of Chemistry, M. V. Lomonosov Moscow State University, Moscow 119991, Russia;2. Department of Chemical Carcinogenesis, Institute of Carcinogenesis, Blokhin Cancer Research Center, Russian Academy of Medical Sciences, Moscow 115478, Russia;1. Department of Chemical Engineering and Food Science, Hubei University of Arts and Science, Xiangyang 441053, PR China;2. State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan University of Technology, Wuhan 430070, PR China;3. Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, PR China;1. Department of Biomedical and Molecular Sciences, Graduate Program in Pharmacology and Toxicology, Queen''s University, Kingston, Ontario, Canada K7L 3N6;2. School of Environmental Studies, Queen''s University, Kingston, Ontario, Canada K7L 3N6
Abstract:Novel DNA intercalating anticancer drug curaxin CBL0137 significantly inhibited in vitro DNA methylation by eukaryotic DNA methyltransferase Dnmt3a catalytic domain (Dnmt3a-CD) at low micromolar concentrations (IC50 3–9 µM). CBL0137 reduced the binding affinity of Dnmt3a-CD to its DNA target, causing up to four-fold increase in the Kd of the enzyme/DNA complex. Binding of CBL0137 to Dnmt3a-CD was not observed. The observed decrease in methylation activity of Dnmt3a-CD in the presence of CBL0137 can be explained by curaxin’s ability to intercalate into DNA.
Keywords:DNA methylation  Dnmt3a-CD  Curaxin  CBL0137  Doxorubicin
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