1083196-75-1Relevant academic research and scientific papers
Inverted positioning of dnmt1 inhibitor in the active site of dnmt1 caused by hydrophobicity/hydrophilicity of the terminal structure
Kondo, Takeshi,Kubo, Yuhei,Tojo, Toshifumi,Yuasa, Makoto
, p. 2372 - 2378 (2021/12/16)
DNA (cytosine-5)-methyltransferase 1 (DNMT1) is one of the enzymes that regulate DNA modification. It has been demonstrated that overexpression of DNMT1 is associated with the development of cancer, making DNMT1 an attractive molecular target for cancer t
Selective non-nucleoside inhibitors of human DNA methyltransferases active in cancer including in cancer stem cells
Valente, Sergio,Liu, Yiwei,Schnekenburger, Michael,Zwergel, Clemens,Cosconati, Sandro,Gros, Christina,Tardugno, Maria,Labella, Donatella,Florean, Cristina,Minden, Steven,Hashimoto, Hideharu,Chang, Yanqi,Zhang, Xing,Kirsch, Gilbert,Novellino, Ettore,Arimondo, Paola B.,Miele, Evelina,Ferretti, Elisabetta,Gulino, Alberto,Diederich, Marc,Cheng, Xiaodong,Mai, Antonello
, p. 701 - 713 (2014/03/21)
DNA methyltransferases (DNMTs) are important enzymes involved in epigenetic control of gene expression and represent valuable targets in cancer chemotherapy. A number of nucleoside DNMT inhibitors (DNMTi) have been studied in cancer, including in cancer stem cells, and two of them (azacytidine and decitabine) have been approved for treatment of myelodysplastic syndromes. However, only a few non-nucleoside DNMTi have been identified so far, and even fewer have been validated in cancer. Through a process of hit-to-lead optimization, we report here the discovery of compound 5 as a potent non-nucleoside DNMTi that is also selective toward other AdoMet-dependent protein methyltransferases. Compound 5 was potent at single-digit micromolar concentrations against a panel of cancer cells and was less toxic in peripheral blood mononuclear cells than two other compounds tested. In mouse medulloblastoma stem cells, 5 inhibited cell growth, whereas related compound 2 showed high cell differentiation. To the best of our knowledge, 2 and 5 are the first non-nucleoside DNMTi tested in a cancer stem cell line.
