Reversible histone acetylation and its inhibitors in myeloid neoplasia

组蛋白的可逆乙酰化是表观遗传调控的关键因素，并已被证明在分子水平上参与髓系疾病的发病机制，包括组蛋白乙酰化和去乙酰化。结合药物化学、体外生物化学、细胞研究和患者血液样本的转化研究，我们希望进一步发展可逆性组蛋白乙酰化在髓系疾病中的作用。我们计划合成有效的选择性组蛋白乙酰转移酶（HATs）抑制剂，并测试其在分离酶、培养白血病细胞和离体培养的患者细胞上的活性。选定的优化抑制剂将在髓系疾病的动物模型中进行测试。这也将用于优化组蛋白去乙酰化酶（hdac）抑制剂和我们在该项目的第一阶段开发的前药。我们将使用检测方法来测量细胞HDAC和HAT活性，以将它们与疾病状态联系起来，特别是来自临床HDAC抑制剂试验的样品与抑制剂反应相关联。该研究项目涵盖了可逆组蛋白乙酰化及其抑制剂的广泛方面，并将进一步了解其抑制剂作为信号研究和潜在药物的工具，以及在翻译研究中使用酶分析。在与来自联盟的生物医学和临床小组的互动中，可以预期高水平的协同作用。

Reversible acetylation of histones is a key element in epigenetic regulation and has been shown to be involved in the pathogenesis of myeloid disease on a molecular level for both histone acetylation and deacetylation. In a combination of medicinal chemistry, in-vitro biochemistry, cellular studies and translational studies on patient blood samples we want to further develop the insight on the role of reversible histone acetylation in myeloid diseases. We plan to synthesize potent and selective inhibitors of histone acetyltransferases (HATs) and test their activity on isolated enzymes, leukemic cells in culture and on patient blasts cultured ex-vivo. Selected optimized inhibitors will be tested in animal models of myeloid disease. This will also be realized for optimized histone deacetylases (HDACs) inhibitors and prodrugs that we have developed in the first phase of the programme. We will use assays to measure cellular HDAC and HAT activity to correlate those with diseases states and especially for samples from clinical HDAC inhibitor trials with inhibitor response. This research program covers a wide range of aspects of reversible histone acetylation and its inhibitors and will bring further knowlege on its inhibitors as tools for signalling studies and potential drugs and on the use of enzymatic assay in translational studies. In interaction with the biomedical and clinical groups from the consortium a high level of synergy can be expected.