Leadership in AD/ADRD Drug Discovery

摘要 此R35领导力应用程序与NIH阿尔茨海默氏症的目标/里程碑中的里程碑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，以 开发新的治疗剂。我们在此应用程序中的首要目标是支持PI 正在斯克里普斯研究公司为AD/ADRD药物发现而聚集，这一活动将在获奖后继续进行 完毕。我们计划的主要里程碑旨在激励计划建设和创建团队建设，以 AD/ADRD药物发现使用斯克里普斯研究和开发公司非常可观的机构资源 它的卡利伯尔药物发现中心。我们还在建设全国一流的研究生院之一 通过我们的指导，利用斯克里普斯排名第一/第二的化学教授，开展药物发现项目- 世界各地的生物化学系。作为可行性的证据，目前FDA批准的六种药物中 AD，其中三个是在PI，也就是利普顿博士的实验室中研发出来的。通过R35领导力应用程序，利普顿博士 是否会指导其他人开发与AD/ADRD相关的药物，以达到改变疾病的新目标 心理治疗。具体地说，利普顿博士将担任新研究员和早期研究人员的研究导师 AD/ADRD药物发现中的研究人员(NI/ESI)。到目前为止，几乎所有的AD/ADRD疗法都在 到目前为止，人类临床试验还没有显示出AD/ADRD的疾病修饰作用。例如，缺乏 到目前为止，以β为中心的疗法在临床试验中的显著疗效需要一个新的范例 开发有效的阿尔茨海默病疗法。为了克服这些知识上的重大差距并取得进展 治疗，AD/ADRD研究人员运作和执行的模型和策略的改进 需要发生。应对这一挑战的一个解决方案是将最好的基础科学家与神经科学方面的培训结合起来， 结构生物学、生物信息学和计算生物学，在制药领域拥有同等的专家团队 在高通量筛选、分析开发、药物化学、化学生物学和 药理学。拥有一个集体和协调的团队，并为初级教员提供重要的指导工作 (NI/ESI)，PI，利普顿博士，已经启动了三项主要努力来解决这一未得到满足的医疗需求，这将是 在当前R35领导力奖申请的支持下进行： ·在此背景下调查、确定和确定潜在的AD/ADRD治疗目标 AD/ADRD的中枢病理生理过程。 ·开展药物发现活动，开发研究用新药(IND)临床候选药物 反复进行目标阐明工作，同时在Scripps药物发现基础设施的基础上构建 做到这一点。 ·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 在斯克里普斯为AD/ADRD设计的药物(目前在美国生物化学新闻中排名第二)。

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).