Core D - Chemical Biology and Therapeutics Innovation Core

总结 化学生物学和治疗学创新核心（核心D）在PP文本中称为“治疗学 核心”将为该计划项目的四个项目提供服务，并与几个 项目负责人完成创新部分。 该核心的长期目标是为各个项目的综合需求提供支持， 目前可用的新的自噬调节剂，验证筛选化合物和命中铅药用 针对不同自噬途径的化学优化和评估这些化合物的影响 通过调节阿尔茨海默病和阿尔茨海默病相关痴呆症中的自噬。 该核心的具体目标是：1）提供一个化学生物学设施，以协助研究人员 该计划项目和核心有机会获得新的自噬调节剂和信息，为他们的适当 制剂和在细胞和体内小鼠研究中的用途。2)为了促进化学品筛选方法， 选择，命中验证，以及目标识别和使用化学生物学方法的参与3）工作 与项目负责人一起验证和扩展命中化合物，并使用 药物化学原理 组成部分：1）化学生物学单元将提供化合物和化学合成 探针、化合物分布、化合物的分析表征和溶解辅助， 2）创新单位将验证，优化和实施不同的 自噬的化学调节剂，使用药物化学进行体内研究， 阿尔茨海默病和阿尔茨海默病相关痴呆症。 服务：核心将协助设计，化学合成，纯化和分析表征 新的自噬调节剂，设计和合成的化学探针的目标识别和 体内接合研究，通过计算药物设计验证命中和命中扩增研究 方法，设计和合成用于结构-活性关系研究的重点化学库， 药物化学的命中铅优化，建议和援助与增溶，正确使用的测定， 药代动力学研究和用于体内评价化合物的配制程序。 相关性：该核心对于本PP开发临床前概念验证的转化工作至关重要 靶向自噬作为预防或延迟阿尔茨海默病发作的有效干预措施的有效性 病理我们预计，用核心产生和测试的铅分子可以为未来的研究奠定基础。 为这种毁灭性的年龄相关疾病开发临床药物。

Summary The Chemical Biology and Therapeutics Innovation Core (Core D) referred in the PP text as “Therapeutics Core” will provide services to the four projects of this Program Project and work collaboratively with several project leaders to accomplish the innovation component. The long-term goal of this core is to provide support for the needs of the individual projects on synthesizing currently available novel autophagy modulators, validating compounds from screening and hit-to-lead medicinal chemistry optimization targeting different autophagy pathways and assessing the impact of these compounds by modulating autophagy in Alzheimer’s disease and Alzheimer’s disease-related dementias. The specific aims of this core are: 1) to provide a chemical biology facility that will assist the investigators of the program projects and cores to have access to novel modulators of autophagy and information for their proper formulation and use in cellular and in vivo mouse studies. 2) to facilitate chemical screening approaches, hit selection, hit validation, and target identification and engagement using chemical biology approaches 3) to work with project leaders for the validation and expansion of hit compounds and hit-to-lead optimization using principles of medicinal chemistry. Components: 1) The chemical biology unit will provide chemical synthesis of compounds and chemical probes, compound distribution, analytical characterization of compounds and assistance with the solubilization, formulation and assay of compounds 2) The innovation unit will validate, optimize and implement different chemical modulators of autophagy using medicinal chemistry towards proof-of-concept in vivo studies for Alzheimer’s disease and Alzheimer’s disease-related dementias. Services: the core will assist with the design, chemical synthesis, purification and analytical characterization of novel autophagy modulators, the design and synthesis of chemical probes for target identification and engagement studies in vivo, validation of hits and hit expansion studies by computational drug design approaches, design and synthesis of focused chemical libraries for structure-activity relationships studies, medicinal chemistry for hit-to-lead optimization, advice and assistance with solubilization, proper use in assays, pharmacokinetic studies, and formulation procedures for evaluation of compounds in vivo. Relevance: This core is essential for the translational efforts of this PP to develop pre-clinical proof-of-concept on the validity of targeting autophagy as an effective intervention to prevent or delay onset of Alzheimer’s disease pathology. We anticipate that lead molecules generated and tested with the core could set the basis for future development clinical drugs for this devastating age-related disorder.