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

San José-Enériz, EdurneAgirre, XabierRabal, ObduliaVilas-Zornoza, AmaiaSanchez-Arias, Juan AMiranda, EstibalizUgarte, AnaRoa, SergioPaiva, BrunoEstella-Hermoso de Mendoza, AnderAlvarez, Rosa MaríaCasares, NoeliaSegura, VictorMartín-Subero, José IOgi, François-XavierSoule, PierreSantiveri, Clara MCampos-Olivas, RamónCastellano, GiancarloGarcía Fernández de Barrena, MaiteRodríguez-Madoz, Juan RobertoGarcía-Barchino, Maria JoséLasarte, Juan JoseAvila, Matias AMartinez-Climent, Jose AngelOyarzabal, JulenProsper, Felipe2018-12-182018-12-182017Nat Commun. 2017; 8: 15424.2041-1723http://hdl.handle.net/20.500.12105/6883The 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.engVoRhttp://creativecommons.org/licenses/by/4.0/AnimalsAntineoplastic AgentsApoptosisCell Line, TumorCell ProliferationCrystallography, X-RayDNA Modification MethylasesDose-Response Relationship, DrugDrug Evaluation, PreclinicalEnzyme InhibitorsEpigenesis, GeneticFemaleHematologic NeoplasmsHistocompatibility AntigensHistone-Lysine N-MethyltransferaseHumansInterferonsMiceMice, Inbred BALB CMicrosomes, LiverMolecular Docking SimulationSurvival AnalysisTreatment OutcomeXenograft Model Antitumor AssaysDrug DesignDiscovery of first-in-class reversible dual small molecule inhibitors against G9a and DNMTs in hematological malignanciesAtribución 4.0 Internacional2854808081542410.1038/ncomms154242041-1723Nature communicationsopen access