DC_05 is a non-nucleoside DNMT1 inhibitor (IC50=10.3 μM) with low micromolar IC50 values and significant selectivity toward other AdoMet-dependent protein methyltransferases.
DNA methyltransferases are responsible for catalyzing the methylation of adenine/cytosine residues in specific regions of the genome, and they participate in the establishment of epigenetic modification patterns. Deregulation of DNA methyltransferase activity will disturb DNA methylation systems, leading to the occurrence of various human diseases including cancers[2] DNA methyltransferase inhibitors have been approved for the treatment of myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myelogenous leukemia[3].DNA methylation is one of the most important epigenetic modifications often occurring on the cytosine of CpG islands located in gene promoter regions, which is thought to be closely correlated with tumorigenesis[4].DNA methylation and histone deacetylation are key epigenetic processes involved in normal cellular function and tumorigenesis. Therapeutic strategies based on DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors are currently in use and under development for the treatment of cancers[5].DC-05 is a DNA methyltransferase 1 (DNMT1) inhibitor, with an IC50 and a Kd of 10.3 μM and 1.09 μM, respectively. DC-05 shows less potent activities against DNMT3A, DNMT3B, G9a, SUV39H1, MLL1, SET7/9, and PRMT1 (IC50: >200, >200, >150, >150, >150, >150, 37.1 μM). DC-05 (1.25, 2.5, 5, and 10 μM) potently inhibits the proliferation of HCT116 (human colon cancer) and Capan-1 (human pancreatic adenocarcinoma cells) after treatment for 24, 48, and 72 h[6].
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