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

Autor: Jose A. Martinez-Climent, Giancarlo Castellano, Xabier Agirre, María José García-Barchino, Estíbaliz Miranda, Victor Segura, Ander Estella-Hermoso de Mendoza, Edurne San José-Enériz, Matías A. Avila, Ramón Campos-Olivas, Clara M. Santiveri, José I. Martín-Subero, Juan A. Sánchez-Arias, Rosa María Alvarez, Juan José Lasarte, Juan R. Rodriguez-Madoz, Ana Ugarte, François-Xavier Ogi, Obdulia Rabal, Bruno Paiva, Sergio Roa, Maite Garcia Fernandez de Barrena, Felipe Prosper, Julen Oyarzabal, Amaia Vilas-Zornoza, Pierre Soule, Noelia Casares
Přispěvatelé: Instituto de Salud Carlos III, Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Fundación La Marató TV3, Centro de Investigación Biomedica en Red - CIBER
Rok vydání: 2017
Předmět:
0301 basic medicine
Methyltransferase
Myeloid
Drug Evaluation
Preclinical
General Physics and Astronomy
Apoptosis
Pharmacology
Crystallography
X-Ray
Epigenesis
Genetic
Mice
Histocompatibility Antigens
hemic and lymphatic diseases
Enzyme Inhibitors
DNA Modification Methylases
Mice
Inbred BALB C
Multidisciplinary
Small molecule
3. Good health
Molecular Docking Simulation
Treatment Outcome
medicine.anatomical_structure
Hematologic Neoplasms
Microsomes
Liver
Immunogenic cell death
Female
Science
Antineoplastic Agents
Biology
Article
General Biochemistry
Genetics and Molecular Biology
03 medical and health sciences
Cell Line
Tumor
medicine
Animals
Humans
Epigenetics
Cell Proliferation
Dose-Response Relationship
Drug
Cell growth
Cancer
Histone-Lysine N-Methyltransferase
General Chemistry
medicine.disease
Survival Analysis
Xenograft Model Antitumor Assays
030104 developmental biology
Drug Design
Interferons
Zdroj: Nature Communications
Nature Communications, Vol 8, Iss 1, Pp 1-10 (2017)
Repisalud
Instituto de Salud Carlos III (ISCIII)
ISSN: 2041-1723
Popis: 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.
Epigenetic drugs are emerging as a powerful therapeutic option for cancer treatment. Here, the authors synthesized selective chemical probes that simultaneously inhibit the G9a and DNMTs methyltransferase activity and demonstrate their anti-tumour activity using in vitro and in vivo models of haematological neoplasia.
Databáze: OpenAIRE
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