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

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.

SUBMITTER: San Jose-Eneriz E 

PROVIDER: S-EPMC5458547 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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

San José-Enériz Edurne E   Agirre Xabier X   Rabal Obdulia O   Vilas-Zornoza Amaia A   Sanchez-Arias Juan A JA   Miranda Estibaliz E   Ugarte Ana A   Roa Sergio S   Paiva Bruno B   Estella-Hermoso de Mendoza Ander A   Alvarez Rosa María RM   Casares Noelia N   Segura Victor V   Martín-Subero José I JI   Ogi François-Xavier FX   Soule Pierre P   Santiveri Clara M CM   Campos-Olivas Ramón R   Castellano Giancarlo G   de Barrena Maite Garcia Fernandez MGF   Rodriguez-Madoz Juan Roberto JR   García-Barchino Maria José MJ   Lasarte Juan Jose JJ   Avila Matias A MA   Martinez-Climent Jose Angel JA   Oyarzabal Julen J   Prosper Felipe F  

Nature communications 20170526

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-27  ...[more]

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