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Selective Non-nucleoside Inhibitors of Human DNA Methyltransferases Active in Cancer Including in Cancer Stem Cells

Sergio Valente 1 Yiwei Liu 2 Michael Schnekenburger 3 Clemens Zwergel 1, 4 Sandro Cosconati 5 Christina Gros 6 Maria Tardugno 1 Donatella Labella 1 Cristina Florean 3 Steven Minden 3 Hideharu Hashimoto 2 Yanqi Chan 2 Xing Zhang 2 Gilbert Kirsch 7 Ettore Novellino 8 Paola B. Arimondo 6 Evelina Miele 9 Elisabetta Ferretti 9 Alberto Gulino 10 Marc Diederich 3, 11 Xiaodong Cheng 2 Antonello Mai 1
1 Department of Medicinal Chemistry and Technologies
2 Emory University [Atlanta, GA]
3 Hôpital Kirchberg
4 LIMBP - Laboratoire d'Ingéniérie Moléculaire et Biochimie Pharmacologique
5 DISTABiF
6 ETaC - Pharmacochimie de la Régulation Epigénétique du Cancer
7 SRSMC - Structure et Réactivité des Systèmes Moléculaires Complexes
8 Department of Pharmacy Naples
9 Università degli Studi di Roma "La Sapienza" [Rome]
10 Department of Genetics
11 SNU - Seoul National University [Seoul]
Abstract : 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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https://hal.univ-lorraine.fr/hal-01494552
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Submitted on : Thursday, March 23, 2017 - 4:19:39 PM
Last modification on : Wednesday, October 28, 2020 - 3:20:08 PM

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Sergio Valente, Yiwei Liu, Michael Schnekenburger, Clemens Zwergel, Sandro Cosconati, et al.. Selective Non-nucleoside Inhibitors of Human DNA Methyltransferases Active in Cancer Including in Cancer Stem Cells. Journal of Medicinal Chemistry, American Chemical Society, 2014, 57 (3), pp.701-713. ⟨10.1021/jm4012627⟩. ⟨hal-01494552⟩

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