National Center for Drug Discovery in Neurodegeneration

国家神经退行性疾病药物发现中心

• 批准号: 7648107
• 负责人: Gregory D Cuny
• 金额: $ 229.96万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-15 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7648107
• 关键词: Academic Medical Centers; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Animal Disease Models; Attention; Automation; Biological Assay; Biotechnology; Budgets; Central Nervous System Diseases; Chemical Agents; Chemicals; Cognitive; Collaborations; Communities; Country; Decision Making; Development; Disease; Drug Industry; Elderly; Elements; Generations; Goals; Home environment; Huntington Disease; Industry; Informatics; Infrastructure Activities; Institution; Intellectual Property; Kansas; Laboratories; Lead; Libraries; Medical; Modeling; Multiple Sclerosis; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurosciences; Operative Surgical Procedures; Parkinson Disease; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Policies; Procedures; Process; Protein Tyrosine Kinase; Publications; Recruitment Activity; Research; Research Infrastructure; Research Personnel; Research Proposals; Resources; Scientist; Screening procedure; Seasons; Series; Staging; Teaching Hospitals; Translations; Universities; Validation; Work; assay development; cytotoxicity; drug candidate; drug development; drug discovery; efficacy testing; falls; high throughput screening; lead series; medical schools; medical specialties; member; motor deficit; neuron loss; parkin gene/protein; polyglutamine; programs; research and development

DESCRIPTION (provided by applicant): Neurodegenerative diseases (ND) are CNS disorders characterized by progressive cell death of neurons that ultimately leads to cognitive and motor deficits. These diseases effect more than 5 million people in the U.S. and by 2010, 20 million people worldwide are projected to suffer from some form of ND. Despite these large numbers, ND remains an unmet medical need, receiving relatively little attention from the pharmaceutical industry. It is clear that the discovery of disease-modifying drugs for ND will require the implementation of a new research model that is not so dependent on industry. One such model has been put into operation in the Laboratory for Drug Discovery in Neurodegeneration (LDDN). The LDDN was established in late 2001 to collaborate with the Harvard Medical School neuroscience community to discover chemical entities that could become the starting points for development into a new generation of drugs to treat ND. During its first two years, the LDDN has worked on no less than twenty projects and launched half-a-dozen medicinal chemistry projects. The LDDN has now reached a critical stage in the development of its drug discovery model where it has become essential to expand its collaborative interactions to include laboratories from around the country and to create a NATIONAL CENTER FOR DRUG DISCOVERY IN NEURODEGENERATION (NCDDN). This proposal outlines the creation of this center and has as its specific aims the establishment of key elements of organizational infrastructure (e.g., steering committee, milestones, sharing of intellectual property, and publication policy) as well as a detailed research plan that will be applied to five new drug discovery projects each year for five years. The drug discovery research of this proposal is driven by close interaction between permanent staff members of the NCDDN and an investigator that comes from the collaborating laboratory. Together, they will extend the discoveries in basic neuroscience that the collaboration investigator (CI) brings to the NCDDN from the "home" lab and (i) develop a precise assay suitable for high-throughput screening, (ii) screen tens of thousands of drug-like molecules that comprise LDDN's growing compound library, (iii) identity and validate screening "hits", and (iv) conduct a limited program of exploratory medicinal chemistry to optimize compound potency. For successful programs, the research plan provides for additional studies that will continue beyond the CI's one year tenure in the NCDDN and include a more extensive program of medicinal chemistry-driven optimization of the lead series of compounds as well as efficacy testing of these compounds in animal models of disease. The final phase of this work, and the over-arching goals of the LDDN and NCDDN, will go beyond the support requested in this application, but will include the crafting of partnerships with industry to bring disease-modifying drugs to patients suffering from ND. In this revised application, we have: (i) specially clarified the nature and operating principles of the Steering Committee, (ii) revised and expanded on the policies relating to the pursuit of intellectual property and the distribution of research-derived materials, (iii) outline more clearly milestones and GO/NOGO decision points for projects, (iv) expanded the resources for medicinal chemistry, and, (iv) described efficacy studies in ammal models and how we will get them done.

描述（由申请人提供）： 神经退行性疾病 (ND) 是一种中枢神经系统疾病，其特征是神经元进行性细胞死亡，最终导致认知和运动缺陷。这些疾病影响着美国超过 500 万人，到 2010 年，预计全世界将有 2000 万人患有某种形式的 ND。尽管数量众多，ND 仍然是一个未满足的医疗需求，受到制药行业的关注相对较少。显然，新城疫疾病缓解药物的发现需要实施一种不太依赖于工业的新研究模式。一种这样的模型已在神经退行性疾病药物发现实验室（LDDN）投入运行。 LDDN 成立于 2001 年底，旨在与哈佛医学院神经科学界合作发现化学实体，这些化学实体可以成为开发新一代治疗 ND 药物的起点。在成立的头两年里，LDDN 已开展了不少于 20 个项目，并启动了 6 个药物化学项目。 LDDN 目前已达到药物发现模型发展的关键阶段，必须扩大其合作互动，将全国各地的实验室纳入其中，并创建国家神经退行性疾病药物发现中心 (NCDDN)。该提案概述了该中心的创建，其具体目标是建立组织基础设施的关键要素（例如指导委员会、里程碑、知识产权共享和出版政策）以及详细的研究计划，该计划将在五年内每年应用于五个新药发现项目。该提案的药物发现研究是由 NCDDN 常任工作人员和来自合作实验室的研究人员之间的密切互动推动的。他们将共同扩展合作研究者 (CI) 从“家庭”实验室为 NCDDN 带来的基础神经科学发现，并 (i) 开发适合高通量筛选的精确测定方法，(ii) 筛选构成 LDDN 不断增长的化合物库的数以万计的药物样分子，(iii) 识别和验证筛选“命中”，以及 (iv) 开展有限的项目 探索性药物化学以优化化合物效力。对于成功的项目，该研究计划提供了额外的研究，这些研究将在 CI 在 NCDDN 的一年任期之后继续进行，包括更广泛的药物化学驱动的先导系列化合物的优化项目以及这些化合物在疾病动物模型中的功效测试。这项工作的最后阶段以及 LDDN 和 NCDDN 的总体目标将超出本申请中所要求的支持范围，但将包括与行业建立合作伙伴关系，为 ND 患者带来疾病缓解药物。 在这份修订后的申请中，我们：（i）特别阐明了指导委员会的性质和运作原则，（ii）修订和扩展了与追求知识产权和研究衍生材料分配相关的政策，（iii）更清晰地概述了项目的里程碑和GO/NOGO决策点，（iv）扩大了药物化学的资源，以及（iv）描述了哺乳动物模型中的功效研究以及我们将如何获得 他们完成了。

项目成果

Development of a mechanism-based high-throughput screen assay for leucine-rich repeat kinase 2--discovery of LRRK2 inhibitors.

开发基于机制的富含亮氨酸重复激酶 2 的高通量筛选测定——LRRK2 抑制剂的发现。

• DOI: 10.1016/j.ab.2010.05.033
• 发表时间: 2010
• 期刊: Analytical biochemistry
• 影响因子: 2.9
• 作者: Liu,Min;Poulose,Shibu;Schuman,Eli;Zaitsev,AlexandraD;Dobson,Brittany;Auerbach,Ken;Seyb,Kathleen;Cuny,GregoryD;Glicksman,MarcieA;Stein,RossL;Yue,Zhenyu
• 通讯作者: Yue,Zhenyu

Identification of small molecule inhibitors of beta-amyloid cytotoxicity through a cell-based high-throughput screening platform.

• DOI: 10.1177/1087057108323909
• 发表时间: 2008-10
• 期刊: Journal of biomolecular screening
• 作者: Seyb KI;Schuman ER;Ni J;Huang MM;Michaelis ML;Glicksman MA
• 通讯作者: Glicksman MA

Structure-activity relationship study of EphB3 receptor tyrosine kinase inhibitors.

• DOI: 10.1016/j.bmcl.2009.09.010
• 发表时间: 2009-11-01
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Qiao L;Choi S;Case A;Gainer TG;Seyb K;Glicksman MA;Lo DC;Stein RL;Cuny GD
• 通讯作者: Cuny GD

Structure-activity relationship study of pyridazine derivatives as glutamate transporter EAAT2 activators.

• DOI: 10.1016/j.bmcl.2011.08.009
• 发表时间: 2011-10-01
• 期刊: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
• 影响因子: 2.7
• 作者: Xing, Xuechao;Chang, Ling-Chu;Kong, Qiongman;Colton, Craig K.;Lai, Liching;Glicksman, Marcie A.;Lin, Chien-Liang Glenn;Cuny, Gregory D.
• 通讯作者: Cuny, Gregory D.

Kinetic mechanistic studies of wild-type leucine-rich repeat kinase 2: characterization of the kinase and GTPase activities.

• DOI: 10.1021/bi901851y
• 发表时间: 2010-03-09
• 期刊: BIOCHEMISTRY
• 影响因子: 2.9
• 作者: Liu, Min;Dobson, Brittany;Glicksman, Marcie A.;Yue, Zhenyu;Stein, Ross L.
• 通讯作者: Stein, Ross L.