Reversible histone acetylation and its inhibitors in myeloid neoplasia

骨髓瘤中的可逆组蛋白乙酰化及其抑制剂

• 批准号: 171267211
• 负责人: Professor Dr. Manfred Jung
• 金额: --
• 依托单位: Institut für Pharmazeutische Wissenschaften
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/171267211?language=en
• 关键词: Reversible; histone; acetylation; its; inhibitors

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.

组蛋白的可逆乙酰化是表观遗传调控中的关键因素，并且已显示在分子水平上参与组蛋白乙酰化和去乙酰化的骨髓疾病的发病机制。在药物化学、体外生物化学、细胞研究和对患者血液样本的转化研究的组合中，我们希望进一步深入了解可逆组蛋白乙酰化在骨髓疾病中的作用。我们计划合成有效的和选择性的组蛋白乙酰转移酶（HAT）抑制剂，并测试其对分离的酶，培养白血病细胞和离体培养的患者胚细胞的活性。将在骨髓疾病的动物模型中测试选定的优化抑制剂。这也将实现优化组蛋白脱乙酰酶（HDAC）抑制剂和前药，我们已经在该计划的第一阶段开发。我们将使用测定来测量细胞HDAC和HAT活性，以将其与疾病状态相关联，特别是对于来自具有抑制剂应答的临床HDAC抑制剂试验的样品。该研究计划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转导研究和潜在药物的工具，以及在翻译研究中使用酶促分析。在与联合会的生物医学和临床小组的互动中，可以预期高度的协同作用。