Area de Hemato-Oncología, Centro de Investigación Médica Aplicada, IDISNA, Ciberonc, Universidad de Navarra, Avenida Pío XII, 55 31008 Pamplona, Spain.
Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research, University of Navarra, Avenida Pío XII, 55 31008 Pamplona, Spain.
Nat Commun. 2017 May 26;8:15424. doi: 10.1038/ncomms15424.
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.
表观遗传学在癌症中的不可争议作用，以及表观遗传改变可以逆转的事实，都有利于开发表观遗传药物。在这项研究中，我们设计并合成了强效、选择性和可逆的化学探针，同时抑制 G9a 和 DNMTs 甲基转移酶的活性。在体外治疗血液系统恶性肿瘤（急性髓细胞白血病-AML、急性淋巴细胞白血病-ALL 和弥漫性大 B 细胞淋巴瘤-DLBCL）时，先导化合物 CM-272 抑制细胞增殖并促进细胞凋亡，诱导干扰素刺激基因和免疫原性细胞死亡。CM-272 显著延长 AML、ALL 和 DLBCL 异种移植模型的存活期。我们的研究结果代表了 G9a/DNMTs 的首创双抑制剂的发现，并确立了这个化学系列作为治疗血液系统肿瘤未满足需求的有前途的治疗工具。
