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

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 () and Felipe Prosper ()
Additional contact information
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

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: 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.

Date: 2017
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/ncomms15424 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15424

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms15424

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().