Open Drug Discovery Center for Alzheimer's Disease

阿尔茨海默病开放药物发现中心

• 批准号: 10250432
• 负责人: ALLAN I LEVEY
• 金额: $ 195.94万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10250432
• 关键词: Address; Affinity; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease therapeutic; Animal Model; Bioinformatics; Biological; Biological Assay; Biology; Biomedical Research; Brain; Cell model; Chemicals; Communities; Custom; Development; Disease; Dose; Environment; Evaluation; Genetic Medicine; Goals; Heart; Home; In Vitro; Intellectual Property; Intervention; Lead; Leadership; Libraries; Ligands; Medicine; Mission; Molecular Target; Neurosciences; North Carolina; Outcome; Patients; Penetration; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Plasma; Property; Protein Kinase; Proteins; Reagent; Research; Risk; Scientist; Site; Structure; Tissues; Ursidae Family; Validation; Work; analog; base; cellular targeting; chemical property; design; drug discovery; in vivo; iterative design; knowledge base; member; new therapeutic target; novel; novel therapeutics; phase I trial; pre-clinical; public-private partnership; screening; structural genomics; targeted treatment; tool; virtual screening

Project Summary/Abstract Drug discovery is an inherently risky endeavor and has proven to be especially so in Alzheimer’s disease (AD). Risk at project inception can be categorized as ‘validation risk’ (the likelihood that modulation of the target will have a favorable outcome in patients) or ‘technical risk’ (the likelihood that a tolerable molecule that modulates the target in patients can be discovered). The Open Drug Discovery Center for Alzheimer’s Disease (Open-AD) initiative will create a set of complementary bioinformatic, structural and pharmacologic tools (high-quality chemical probes) to evaluate a diverse set of AD hypotheses in an open discovery environment. Creation of high-quality chemical probes that are active in cellular and animal models of AD versus less explored targets can decrease the technical and validation risk inherent in discovery of new drugs for this disease. Scientists in the Med Chem Core have been successful in developing and sharing freely with the scientific community first-in-class chemical probes unburdened by intellectual property. We are committed to exploring our overarching hypothesis that open drug discovery will accelerate the development of AD medicines through robust and independent evaluation of a diverse set of untested AD therapeutic hypotheses utilizing the most impactful of all tools; a high-quality, cellular and in vivo active chemical probes. Aim 1. Portfolio creation: The Med Chem Core will work closely with the Bioinf and Struct Bio Cores to select a portfolio of novel AD related targets such that 6 targets enter the hit discovery phase each year. Targets will be vetted for the technical risk of probe discovery and prioritized for screening based upon this and the disease validation risk. Aim 2. Hit discovery: The Assay and Screen Core will take the lead on diversity-based HTS for hit discovery. The Med Chem Core will therefore focus on complementary, knowledge-based approaches, such as: virtual screening, focused screening using custom libraries, optimization of fragment-based hits discovered in the Struct Bio Core, structure-guided ligand design, and other rationale approaches. Aim 3. Hit to probe: The Med Chem Core will apply state-of-the-art medicinal chemistry strategies to iteratively design sets of drug-like analogues with physical-chemical properties consistent with CNS penetration. These will be assessed in a hierarchy of assays to address target affinity, selectivity, cellular activity, and in vitro ADME properties. As compounds achieve the desired activity in these assays, they will advance into in vivo assessment of plasma/brain PK and target engagement. Final probes will be extensively characterized to support their MOA and efficacy by the Assay and Screen Core in models of AD. The overall goal of the Med Chem Core is to deliver 3 cellular and 1-2 in vivo probes per year versus novel targets implicated in AD, which will be made freely available to the scientific community. ! 1!

项目概要/摘要 药物发现本质上是一项充满风险的工作，事实证明，在阿尔茨海默病 (AD) 领域尤其如此。 项目开始时的风险可以归类为“验证风险”（目标的调整将导致风险的可能性） 对患者有良好的结果）或“技术风险”（调节可耐受分子的可能性） 可以发现患者体内的目标）。阿尔茨海默病开放药物发现中心 (Open-AD) 该倡议将创建一套互补的生物信息学、结构和药理学工具（高质量 化学探针）以在开放的发现环境中评估各种 AD 假设。创造 与较少探索的目标相比，在 AD 细胞和动物模型中活跃的高质量化学探针 可以降低针对这种疾病的新药发现中固有的技术和验证风险。 医学化学核心的科学家们已经成功地开发并与科学界自由分享 社区一流的不受知识产权负担的化学探针。我们致力于探索 我们的总体假设是开放式药物发现将加速 AD 药物的开发 通过对各种未经检验的 AD 治疗假设进行稳健和独立的评估 利用所有工具中最具影响力的工具；高质量的细胞和体内活性化学探针。 目标 1. 组合创建：Med Chem 核心将与 Bioinf 和 Struct Bio 核心密切合作， 选择一系列新的 AD 相关目标，每年有 6 个目标进入热门发现阶段。目标 将审查探针发现的技术风险，并根据此和优先级进行筛选 疾病验证风险。 目标 2. 命中发现：Assay and Screen Core 将在基于多样性的 HTS 方面处于领先地位，以进行命中发现。 因此，医学化学核心将重点关注互补的、基于知识的方法，例如：虚拟 筛选、使用自定义库进行集中筛选、优化在 Struct Bio Core、结构引导配体设计和其他基本原理方法。 目标 3. 命中探索：Med Chem Core 将应用最先进的药物化学策略迭代 设计具有与中枢神经系统渗透一致的物理化学特性的类药物类似物。这些将 在一系列测定中进行评估，以解决目标亲和力、选择性、细胞活性和体外 ADME 特性。当化合物在这些测定中达到所需的活性时，它们将进入体内评估 血浆/大脑 PK 和目标参与度。最终探针将被广泛表征以支持其 MOA 以及 AD 模型中 Assay 和 Screen Core 的功效。 Med Chem Core 的总体目标是每年提供 3 个细胞探针和 1-2 个体内探针（与新型探针相比） AD 中涉及的目标，将免费提供给科学界。 ！ 1！