title: Selective non-nucleoside inhibitors of human DNA methyltransferases active in cancer including in cancer stem cells.
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 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.
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma , P.le Aldo Moro 5, 00185 Roma, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Valente
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Liu
authors.forename: Michael
authors.initials: M
authors.lastname: Schnekenburger
authors.forename: Clemens
authors.initials: C
authors.lastname: Zwergel
authors.forename: Sandro
authors.initials: S
authors.lastname: Cosconati
authors.forename: Christina
authors.initials: C
authors.lastname: Gros
authors.forename: Maria
authors.initials: M
authors.lastname: Tardugno
authors.forename: Donatella
authors.initials: D
authors.lastname: Labella
authors.forename: Cristina
authors.initials: C
authors.lastname: Florean
authors.forename: Steven
authors.initials: S
authors.lastname: Minden
authors.forename: Hideharu
authors.initials: H
authors.lastname: Hashimoto
authors.forename: Yanqi
authors.initials: Y
authors.lastname: Chang
authors.forename: Xing
authors.initials: X
authors.lastname: Zhang
authors.forename: Gilbert
authors.initials: G
authors.lastname: Kirsch
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Paola B
authors.initials: PB
authors.lastname: Arimondo
authors.forename: Evelina
authors.initials: E
authors.lastname: Miele
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ferretti
authors.forename: Alberto
authors.initials: A
authors.lastname: Gulino
authors.forename: Marc
authors.initials: M
authors.lastname: Diederich
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Cheng
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000634:Aminoquinolines; D000970:Antineoplastic Agents; D001549:Benzamides; C587722:N-(3-(2-amino-6-methylpyrimidin-4-ylamino)phenyl)-4-(quinolin-4-ylamino)benzamide; D011743:Pyrimidines; D011804:Quinolines; D004248:DNA (Cytosine-5-)-Methyltransferases