Selective Non-nucleoside Inhibitors of Human DNA Methyltransferases Active in Cancer Including in Cancer Stem Cells
| Autor: | Xiaodong Cheng, Marc Diederich, Michael Schnekenburger, Christina Gros, Gilbert Kirsch, Clemens Zwergel, Yanqi Chang, Hideharu Hashimoto, Sergio Valente, Maria Tardugno, Xing Zhang, Yiwei Liu, Ettore Novellino, Antonello Mai, Donatella Labella, Cristina Florean, Sandro Cosconati, Evelina Miele, Steven Minden, Alberto Gulino, Paola B. Arimondo, Elisabetta Ferretti |
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| Přispěvatelé: | Valente, S, Liu, Y, Schnekenburger, M, Zwergel, C, Cosconati, Sandro, Gros, C, Tardugno, M, Labella, D, Florean, C, Minden, S, Hashimoto, H, Chan, Y, Zhang, X, Kirsch, G, Novellino, E, Arimondo, Pb, Miele, E, Ferretti, E, Gulino, A, Diederich, M, Cheng, X, Mai, A., Department of Medicinal Chemistry and Technologies, Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Emory University [Atlanta, GA], Hôpital Kirchberg, Hôpital Kirchberg [Luxembourg], Laboratoire d'Ingéniérie Moléculaire et Biochimie Pharmacologique (LIMBP), Université Paul Verlaine - Metz (UPVM), DISTABiF, Seconda Universita di Napoli, Pharmacochimie de la Régulation Epigénétique du Cancer (ETaC), PIERRE FABRE-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Structure et Réactivité des Systèmes Moléculaires Complexes (SRSMC), Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Department of Pharmacy Naples, Université de Naples, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Department of Genetics, Portuguese Oncology Institute, Seoul National University [Seoul] (SNU), Sergio, Valente, Yiwei, Liu, Michael, Schnekenburger, Clemens, Zwergel, Sandro, Cosconati, Christina, Gro, Maria, Tardugno, Donatella, Labella, Cristina, Florean, Steven, Minden, Hideharu, Hashimoto, Yanqi, Chang, Xing, Zhang, Gilbert, Kirsch, Novellino, Ettore, Paola B., Arimondo, Evelina, Miele, Elisabetta, Ferretti, Alberto, Gulino, Marc, Diederich, Xiaodong, Cheng, Antonello, Mai |
| Rok vydání: | 2014 |
| Předmět: |
Methyltransferase
Decitabine Antineoplastic Agents Pharmacology Article Mice Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Cancer stem cell Cell Line Tumor Drug Discovery medicine [CHIM]Chemical Sciences Animals Humans DNA (Cytosine-5-)-Methyltransferases 030304 developmental biology 0303 health sciences Cell growth Chemistry Cancer medicine.disease 3. Good health Pyrimidines Cell culture 030220 oncology & carcinogenesis Benzamides Cancer cell Aminoquinolines Neoplastic Stem Cells Quinolines Molecular Medicine Drug Screening Assays Antitumor Stem cell medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry Journal of Medicinal Chemistry, American Chemical Society, 2014, 57 (3), pp.701-713. ⟨10.1021/jm4012627⟩ Journal of Medicinal Chemistry; Vol 57 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm4012627 |
| Popis: | 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. © 2014 American Chemical Society. |
| Databáze: | OpenAIRE |
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