基于激酶LRRK2为靶标的帕金森症靶向药物研究

项目名称： 基于激酶LRRK2为靶标的帕金森症靶向药物研究

项目编号： No.21272195

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 数理科学和化学

项目作者： 邓贤明

作者单位： 厦门大学

项目金额： 80万元

中文摘要： 帕金森症是世界第二大神经退行性运动障碍疾病，随着人口的老龄化，预计帕金森症的发病率在未来的几十年将大大增加。当前以多巴胺疗法为主的治疗策略，远不能满足实际需求，发展新的治疗方法是帕金森症研究的当务之急。医学基因组学研究表明具有激酶活性的LRRK2基因有望成为攻克帕金森症的靶标。激酶抑制剂作为抗肿瘤"靶向"药物的巨大成功启发了我们开展以LRRK2为"靶标"的帕金森症靶向药物的探索。我们的前期工作发展了高活性、高选择性的激酶LRRK2的抑制剂，但由于不能有效穿透血脑屏障限制了它在帕金森症动物模型中的应用。在此基础上，我们将从导向化合物库的设计、合成出发，运用"化合物为中心"的筛选策略，发展具有良好穿透血脑屏障特性的LRRK2小分子抑制剂，并以其为化学探针研究LRRK2与帕金森症相关的信号传导途径，探讨LRRK2抑制剂作为靶向药物的可行性。该研究将为发展针对LRRK2的帕金森症靶向疗法奠定基础。

中文关键词： 帕金森症；激酶抑制剂；靶向药物；激酶LRRK2；信号传导

英文摘要： Parkinson's disease (PD) is the second most common neurodegenerative disorder. With the aging of the population, the frequency of PD is expected to increase dramatically in the coming decades. Current therapy is largely based on a dopamine replacement strategy, there's an urgent need to develop new therapeutic intervention. Recent genetic studies have revealed that LRRK2 gene with kinase activity could be a promising target for developing new therapy of PD. The great success of kinase inhibitors as targeted therapy for cancer promotes the development of LRRK2 inhibitors as targeted therapy for PD. Previously, we have developed a selective LRRK2 inhibitor, LRRK2-IN-1, with potent activity in vitro and cells, but LRRK2-IN-1 was limited because of poor blood brain barrier (BBB) property. Here, we propose to develop LRRK2 inhibitor that have the ability to traverse the BBB using 'compound centric' profiling strategy, which starts with the design and synthesis of focus library. We will also employ the inhibitor from this study to delineate the LRRK2 signaling pathway and test this inhibitor in PD-related animal model. Taken together, these studies will provide a chemical tool to study LRRK2 biology and uncover the physiological and pathogenic role of LRRK2 in PD. This will lay the foundation of developing new target

英文关键词： Parkinson's disease；kinase inhibitor；targeted therapeutic；LRRK2；signal transduction