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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Apoptosis / drug effects
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Apoptosis / genetics
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Apoptosis / immunology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Proliferation / genetics
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Crystallography, X-Ray
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DNA Modification Methylases / antagonists & inhibitors*
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DNA Modification Methylases / chemistry
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DNA Modification Methylases / genetics
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DNA Modification Methylases / metabolism
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Dose-Response Relationship, Drug
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Drug Design*
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Drug Evaluation, Preclinical
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Enzyme Inhibitors / therapeutic use
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Epigenesis, Genetic / drug effects
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Female
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Hematologic Neoplasms / drug therapy*
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Hematologic Neoplasms / genetics
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Hematologic Neoplasms / immunology
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Hematologic Neoplasms / mortality
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Histocompatibility Antigens / chemistry
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Histocompatibility Antigens / genetics
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Histocompatibility Antigens / metabolism
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Histone-Lysine N-Methyltransferase / antagonists & inhibitors*
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Histone-Lysine N-Methyltransferase / chemistry
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Histone-Lysine N-Methyltransferase / genetics
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Histone-Lysine N-Methyltransferase / metabolism
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Humans
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Interferons / immunology
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Interferons / metabolism
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Mice
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Mice, Inbred BALB C
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Microsomes, Liver
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Molecular Docking Simulation
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Survival Analysis
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Treatment Outcome
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Enzyme Inhibitors
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Histocompatibility Antigens
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Interferons
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DNA Modification Methylases
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EHMT2 protein, human
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Histone-Lysine N-Methyltransferase