3 years ago

Discovery of first-in-class reversible dual small molecule inhibitors against G9a and DNMTs in hematological malignancies

Discovery of first-in-class reversible dual small molecule inhibitors against G9a and DNMTs in hematological malignancies
Edurne San José-Enériz, Pierre Soule, Clara M. Santiveri, Sergio Roa, Bruno Paiva, Rosa María Alvarez, Estibaliz Miranda, Noelia Casares, Obdulia Rabal, Matias A Avila, Xabier Agirre, Amaia Vilas-Zornoza, Ana Ugarte, Ander Estella-Hermoso de Mendoza, Maite Garcia Fernandez de Barrena, Julen Oyarzabal, François-Xavier Ogi, José I. Martín-Subero, Victor Segura, Jose Angel Martinez-Climent, Juan Roberto Rodriguez-Madoz, Maria José García-Barchino, Juan Jose Lasarte, Ramón Campos-Olivas, Giancarlo Castellano, Juan A. Sanchez-Arias, Felipe Prosper
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.

Publisher URL: http://www.nature.com/articles/ncomms15424

DOI: 10.1038/ncomms15424

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