Erdmann Alexandre, Menon Yoann, Gros Christina, Masson Véronique, Aussagues Yannick, Ausseil Fréderic, Novosad Natacha, Schambel Philippe, Baltas Michel, Arimondo Paola B
Unité de Service et de Recherche CNRS-Pierre Fabre USR n°3388, ETaC, CRDPF, 31100 Toulouse, France.
Institut de Recherche Pierre Fabre, 81106 Castres, France.
Future Med Chem. 2016;8(4):373-80. doi: 10.4155/fmc.15.192. Epub 2016 Mar 15.
DNA methylation is the most studied epigenetic event. Since the methylation profile of the genome is widely modified in cancer cells, DNA methyltransferases are the target of new anticancer therapies. Nucleosidic inhibitors suffer from toxicity and chemical stability, while non-nucleosidic inhibitors lack potency. Here, we found a novel DNMT inhibitor scaffold by enzymatic screening and structure-activity relationship studies. The optimization studies led to an inhibitor containing three fragments: a gallate frame, a hydrazone linker and a benzothiazole moiety. Interestingly, the compound inhibits DNMT3A with micromolar potency (EC50 = 1.6 μM) and does not inhibit DNMT1; this DNMT3A selectivity is supported by a docking study. Finally, the compound reactivates a reporter gene in leukemia KG-1 cells.
DNA甲基化是研究最为广泛的表观遗传事件。由于癌细胞中基因组的甲基化谱被广泛改变，DNA甲基转移酶成为新型抗癌疗法的靶点。核苷类抑制剂存在毒性和化学稳定性问题，而非核苷类抑制剂则缺乏效力。在此，我们通过酶筛选和构效关系研究发现了一种新型的DNA甲基转移酶（DNMT）抑制剂骨架。优化研究得到了一种含有三个片段的抑制剂：没食子酸盐框架、腙连接体和苯并噻唑部分。有趣的是，该化合物对DNMT3A具有微摩尔级别的抑制效力（EC50 = 1.6 μM），且不抑制DNMT1；对接研究证实了这种对DNMT3A的选择性。最后，该化合物可使白血病KG-1细胞中的报告基因重新激活。
