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

Author

Listed:
  • Edurne San José-Enériz

    (Area de Hemato-Oncología, Centro de Investigación Médica Aplicada, IDISNA, Ciberonc, Universidad de Navarra)

  • Xabier Agirre

    (Area de Hemato-Oncología, Centro de Investigación Médica Aplicada, IDISNA, Ciberonc, Universidad de Navarra)

  • Obdulia Rabal

    (Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research, University of Navarra)

  • Amaia Vilas-Zornoza

    (Area de Hemato-Oncología, Centro de Investigación Médica Aplicada, IDISNA, Ciberonc, Universidad de Navarra)

  • Juan A. Sanchez-Arias

    (Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research, University of Navarra)

  • Estibaliz Miranda

    (Area de Hemato-Oncología, Centro de Investigación Médica Aplicada, IDISNA, Ciberonc, Universidad de Navarra)

  • Ana Ugarte

    (Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research, University of Navarra)

  • Sergio Roa

    (Area de Hemato-Oncología, Centro de Investigación Médica Aplicada, IDISNA, Ciberonc, Universidad de Navarra)

  • Bruno Paiva

    (Area de Hemato-Oncología, Centro de Investigación Médica Aplicada, IDISNA, Ciberonc, Universidad de Navarra)

  • Ander Estella-Hermoso de Mendoza

    (Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research, University of Navarra)

  • Rosa María Alvarez

    (Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research, University of Navarra)

  • Noelia Casares

    (Area de Terapia Génica y Hepatología, Centro de Investigación Médica Aplicada, Universidad de Navarra)

  • Victor Segura

    (Unidad de Bioinformática, Centro de Investigación Médica Aplicada, Universidad de Navarra)

  • José I. Martín-Subero

    (Universitat de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer)

  • François-Xavier Ogi

    (Nanotemper Technologies GmbH)

  • Pierre Soule

    (Nanotemper Technologies GmbH)

  • Clara M. Santiveri

    (Spectroscopy and NMR Unit, Spanish National Cancer Research Center (CNIO))

  • Ramón Campos-Olivas

    (Spectroscopy and NMR Unit, Spanish National Cancer Research Center (CNIO))

  • Giancarlo Castellano

    (Universitat de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer)

  • Maite Garcia Fernandez de Barrena

    (Area de Terapia Génica y Hepatología, Centro de Investigación Médica Aplicada, Universidad de Navarra)

  • Juan Roberto Rodriguez-Madoz

    (Area de Hemato-Oncología, Centro de Investigación Médica Aplicada, IDISNA, Ciberonc, Universidad de Navarra)

  • Maria José García-Barchino

    (Area de Hemato-Oncología, Centro de Investigación Médica Aplicada, IDISNA, Ciberonc, Universidad de Navarra)

  • Juan Jose Lasarte

    (Area de Terapia Génica y Hepatología, Centro de Investigación Médica Aplicada, Universidad de Navarra)

  • Matias A Avila

    (Area de Terapia Génica y Hepatología, Centro de Investigación Médica Aplicada, Universidad de Navarra)

  • Jose Angel Martinez-Climent

    (Area de Hemato-Oncología, Centro de Investigación Médica Aplicada, IDISNA, Ciberonc, Universidad de Navarra)

  • Julen Oyarzabal

    (Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research, University of Navarra)

  • Felipe Prosper

    (Area de Hemato-Oncología, Centro de Investigación Médica Aplicada, IDISNA, Ciberonc, Universidad de Navarra
    Clínica Universidad de Navarra, Universidad de Navarra)

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.

Suggested Citation

  • 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 & Ro, 2017. "Discovery of first-in-class reversible dual small molecule inhibitors against G9a and DNMTs in hematological malignancies," Nature Communications, Nature, vol. 8(1), pages 1-10, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15424
    DOI: 10.1038/ncomms15424
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