Leadership in AD/ADRD Drug Discovery

AD/ADRD 药物发现领域的领导地位

• 批准号: 10687169
• 负责人: STUART A LIPTON
• 金额: $ 108.36万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10687169
• 关键词: Address; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; American; Amyloid beta-Protein; Award; Biochemistry; Bioinformatics; Biology; California; Chemicals; Chemistry; Clinical Trials; Computational Biology; Development; Disease; Drug Design; Drug Industry; FDA approved; Faculty; Goals; Human; Infrastructure; Institution; Investigation; Investigational Drugs; Knowledge; Laboratories; Leadership; Medical; Medicine; Mentors; Modeling; Neurodegenerative Disorders; Neurosciences; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Prevalence; Process; Research; Research Personnel; Resources; Scientist; Therapeutic; Therapeutic Agents; Training; United States National Institutes of Health; assay development; clinical candidate; drug action; drug development; drug discovery; graduate school; high throughput screening; improved; news; novel; novel therapeutics; programs; structural biology; symposium; therapeutic target; virtual

SUMMARY This R35 leadership application is relevant to Milestone 6D of the goals/milestones of the NIH Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD) Summits—“Initiate drug discovery efforts to develop novel therapeutic agents.” Our overriding goal in this application is to support the infrastructure the PI is assembling for AD/ADRD drug discovery at Scripps Research, which will continue well after the award is over. Our major planned milestone is aimed to INSPIRE program building and create team building for AD/ADRD Drug Discovery using the very considerable institutional resources at Scripps Research and its Calibr Drug Discovery Center. We are also building one of the nation’s top-ranked Graduate School programs in drug discovery via our mentoring using the faculty of Scripps’ #1/#2-ranked chemistry- biochemistry departments in the world. As proof of feasibility, of the six currently FDA-approved medicines for AD, three were developed out of the PI, Dr. Lipton’s laboratory. Via this R35 Leadership Application, Dr. Lipton will mentor others to develop AD/ADRD-related drugs acting at novel targets toward disease-modifying therapy. Specifically, Dr. Lipton will serve as research mentor for New Investigators and Early Stage Investigators (NI/ESI) in AD/ADRD drug discovery. To date, virtually all AD/ADRD therapeutics evaluated in human clinical trials have so far failed to show disease-modifying effects for AD/ADRD. For example, the lack of significant efficacy in clinical trials with Aβ-centered therapeutics to date demands a new paradigm for development of effective AD therapeutics. To overcome these significant gaps in knowledge and to advance therapies, improvements in the models and strategies by which AD/ADRD researchers function and execute need to occur. One solution to this challenge is to unite the best basic scientists with training in neuroscience, structural biology, bioinformatics and computational biology, with equally expert teams in the pharmaceutical industry trained in high-throughput screening, assay development, medicinal chemistry, chemical biology and pharmacology. With a collective and harmonized team along with significant mentoring efforts for junior faculty (NI/ESI), the PI, Dr. Lipton, has initiated three major efforts to address this unmet medical need, which will be carried out under the auspices of the current R35 Leadership Award application: · Investigation, identification and characterization of potential AD/ADRD therapeutic targets in the context of the central pathophysiological processes in AD/ADRD. · Execution of drug discovery campaigns to develop investigational new drug (IND) clinical candidates iteratively with the target elucidation efforts, while building upon Scripps drug discovery infrastructure to accomplish this. · Continue to mentor junior faculty and build a world-class graduate school around the chemical biology of drug design for AD/ADRD at Scripps (currently ranked #2 by US News for Biochemistry).

概括 该R35领导力应用与NIH阿尔茨海默氏症的目标/里程碑的里程碑6D有关 疾病和阿尔茨海默氏病有关的痴呆症（AD/ADRD）峰会 - “启动药物发现工作 开发新颖的治疗剂。 正在Scripps Research组装AD/ADRD药物发现，该奖项将在奖励之后继续 超过。我们的主要计划中的里程碑旨在激发计划建设并为 使用Scripps Research和 它的校准药物发现中心。我们还正在建立全美排名最高的研究生院之一 使用Scripps的＃1/＃2排名化学学院通过我们的心理发现中的药物发现计划 - 世界上的生物化学部门。作为可行性的证明，目前是FDA批准的六种药物 Lipton博士的实验室，AD，三个是由PI开发的。通过此R35领导申请，Lipton博士 将指导其他人开发出针对疾病改良的新靶标的AD/ADRD相关药物 治疗。特别是，Lipton博士将担任新研究人员和早期的研究导师 AD/ADRD药物发现中的研究人员（NI/ESI）。迄今为止，几乎所有评估的AD/ADRD疗法 到目前为止，人类的临床试验未能显示出对AD/ADRD的疾病改良作用。例如，缺乏 迄今为止，以Aβ为中心的治疗的临床试验中的效率显着 开发有效的广告疗法。克服这些重大差距并促进 AD/ADRD研究人员发挥作用和执行的疗法，改进模型和策略 需要发生。解决这一挑战的一种解决方案是将最佳基础科学家与神经科学的培训团结起来， 结构生物学，生物信息学和计算生物学，在药品中拥有平等的专家团队 经过高通量筛查，测定开发，医学化学，化学生物学和 药理。与集体和协调的团队一起为初级教师做重大的心理努力 （Ni/Esi），Pi，Lipton博士，已经开始了三项重大努力，以满足这种未满足的医疗需求，这将是 根据当前R35领导奖申请的主持人进行： 在上下文 AD/ADRD中的中央病理生理过程。 执行药物发现运动以开发研究性新药（IND）临床候选者 在目标阐明工作的同时迭代地阐明，同时在Scripps毒品发现基础设施上 做到这一点。 继续学习精神少年教师，并在化学生物学周围建立世界一流的研究生院 Scripps的AD/ADRD的药物设计（目前由美国新闻的生物化学新闻排名第二）。