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 此 R35 领导力应用程序与 NIH 阿尔茨海默病目标/里程碑的里程碑 6D 相关 疾病和阿尔茨海默病相关痴呆 (AD/ADRD) 峰会——“启动药物发现工作 开发新型治疗药物。”我们在此应用中的首要目标是支持 PI 的基础设施。 斯克里普斯研究中心正在集结 AD/ADRD 药物发现，该工作将在获奖后继续进行 我们计划的主要里程碑旨在激发计划建设并创建团队建设。 AD/ADRD 药物发现利用斯克里普斯研究中心的大量机构资源 我们还正在建设美国顶尖的研究生院之一。 通过我们使用斯克里普斯#1/#2排名的化学系的指导来开展药物发现项目- 作为可行性证明，目前 FDA 批准了六种药物。 AD，其中三个是由 PI、Lipton 博士的实验室通过 R35 领导力应用程序开发的。 将指导其他人开发针对新靶点的 AD/ADRD 相关药物，以改善疾病 具体来说，利普顿博士将担任新研究者和早期阶段的研究导师。 AD/ADRD 药物发现领域的研究者 (NI/ESI) 迄今为止，几乎所有 AD/ADRD 疗法都经过了评估。 迄今为止，人类临床试验尚未显示出对 AD/ADRD 的疾病缓解作用。 迄今为止，以 Aβ 为中心的疗法在临床试验中取得显着疗效，需要一个新的范例 开发有效的 AD 疗法，以克服这些重大的知识差距并取得进展。 AD/ADRD 研究人员运作和执行的疗法、模型和策略的改进 应对这一挑战的一个解决方案是将最优秀的基础科学家与神经科学培训结合起来， 结构生物学、生物信息学和计算生物学，以及制药领域同样的专家团队 在高通量筛选、分析开发、药物化学、化学生物学和 拥有一个集体和协调的团队以及对初级教师的大力指导。 (NI/ESI)，PI，Lipton 博士，已发起三项重大努力来解决这一未满足的医疗需求，这将是 在当前 R35 领导奖申请的赞助下进行： · 背景下潜在 AD/ADRD 治疗靶点的调查、识别和表征 AD/ADRD 的主要病理生理过程。 · 对研究性新药 (IND) 临床候选药物开展药物发现活动 迭代地进行目标阐明工作，同时建立在斯克里普斯药物发现基础设施的基础上 完成这个。 · 继续指导初级教师，围绕化学生物学建设世界一流的研究生院 斯克里普斯的 AD/ADRD 药物设计博士（目前在《美国生物化学新闻》中排名第二）。