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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-05-26

AUTHORS

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

ABSTRACT

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. More... »

PAGES

15424

References to SciGraph publications

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  • Journal

    TITLE

    Nature Communications

    ISSUE

    1

    VOLUME

    8

    Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/ncomms15424

    DOI

    http://dx.doi.org/10.1038/ncomms15424

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1085594512

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/28548080


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