Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 57, Issue 3, Pages 701-713Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm4012627
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Funding
- FIRB [RBFR10ZJQT]
- FP7 [BLUEPRINT/282510, COST/TD0905]
- FP7Marie Curie [REDCAT/215009]
- Sapienza-IIT Project
- Televie Luxembourg
- Recherche Cancer et Sang Foundation
- Recherches Scientifiques Luxembourg
- Een Haerz fir Kriibskrank Kanner
- U.S. National Institutes of Health [GM049245-20, DK094346-01]
- Action Lions Vaincre le Cancer
- Ministere de la Culture, de l'Enseignement superieur et de la Recherche du Luxembourg
- NRF from MEST [GCRC 2012-0001184]
- Seoul National University research grant
- Research Settlement Fund for the new faculty of SNU
- French Region Midi-Pyrenees (Equipe d'Excellence et FEDER)
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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 Ado Met-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.
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