Discovery of first-in-class reversible dual small molecule inhibitors against G9a and DNMTs in hematological malignancies.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 28548080.
- Also identified by DOI 10.1038/ncomms15424 and PMC identifier 5458547.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- Antineoplastic Agents
- DNA Modification Methylases
- Drug Design
- Enzyme Inhibitors
- Hematologic Neoplasms
- Histone-Lysine N-Methyltransferase