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oai:repisalud.isciii.es:20.500.12105/68832024-11-29T16:28:14Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc San José-Enériz, Edurne author Agirre, Xabier author Rabal, Obdulia author Vilas-Zornoza, Amaia author Sanchez-Arias, Juan A author Miranda, Estibaliz author Ugarte, Ana author Roa, Sergio author Paiva, Bruno author Estella-Hermoso de Mendoza, Ander author Alvarez, Rosa María author Casares, Noelia author Segura, Victor author Martín-Subero, José I author Ogi, François-Xavier author Soule, Pierre author Santiveri, Clara M author Campos-Olivas, Ramón author Castellano, Giancarlo author García Fernández de Barrena, Maite author Rodríguez-Madoz, Juan Roberto author García-Barchino, Maria José author Lasarte, Juan Jose author Avila, Matias A author Martinez-Climent, Jose Angel author Oyarzabal, Julen author Prosper, Felipe author 2017 The indisputable role of epigenetics in cancer and the fact that epigenetic alterations can be reversed have favoured development of epigenetic drugs. In this study, we design and synthesize potent novel, selective and reversible chemical probes that simultaneously inhibit the G9a and DNMTs methyltransferase activity. In vitro treatment of haematological neoplasia (acute myeloid leukaemia-AML, acute lymphoblastic leukaemia-ALL and diffuse large B-cell lymphoma-DLBCL) with the lead compound CM-272, inhibits cell proliferation and promotes apoptosis, inducing interferon-stimulated genes and immunogenic cell death. CM-272 significantly prolongs survival of AML, ALL and DLBCL xenogeneic models. Our results represent the discovery of first-in-class dual inhibitors of G9a/DNMTs and establish this chemical series as a promising therapeutic tool for unmet needs in haematological tumours. Nat Commun. 2017; 8: 15424. 2041-1723 http://hdl.handle.net/20.500.12105/6883 28548080 10.1038/ncomms15424 2041-1723 Nature communications Discovery of first-in-class reversible dual small molecule inhibitors against G9a and DNMTs in hematological malignancies