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 |
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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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