Brain-penetrant chemical disaggregators of tau fibrils as therapeutics for Alzheimer's Disease

tau 原纤维的脑渗透化学分解剂作为阿尔茨海默氏病的治疗方法

• 批准号: 10384228
• 负责人: MARCIN APOSTOL
• 金额: $ 47.66万
• 依托单位: ADRX, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10384228
• 关键词: Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease therapeutic; Animal Model; Antibodies; Binding; Binding Sites; Biological Assay; Biota; Blood - brain barrier anatomy; Brain; Cells; Characteristics; Chemicals; Clinic; Clinical Trials; Cognitive; Complex; Cryoelectron Microscopy; Dementia; Disease; Disease Progression; Docking; Drug Targeting; Electrons; Epigallocatechin Gallate; Evaluation; Face; Failure; Family Caregiver; Family member; Foundations; Gallic acid; Goals; Hybrids; Image; Impaired cognition; Incubated; Intestines; Lead; Medical; Metabolic; Metabolism; Methods; Molecular Structure; Motor; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Oral; Patients; Permeability; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Property; Research; Senile Plaques; Series; Signal Transduction; Site; Small Business Innovation Research Grant; Structure; Tauopathies; Testing; Therapeutic Agents; Time; Toxic effect; Translations; United States; Validation; Work; base; blood-brain barrier penetration; cerebral atrophy; density; design; drug candidate; drug development; economic impact; effective therapy; extracellular; human old age (65+); in silico; in vitro activity; in vivo; inhibitor; insight; neuron loss; novel; pharmacokinetics and pharmacodynamics; pharmacophore; phase 1 study; pill; polyphenol; screening; small molecule; small molecule therapeutics; structural biology; tau Proteins; tau aggregation

ABSTRACT Alzheimer’s disease is a multifactorial disease in which numerous mechanisms culminate in neuronal death, brain atrophy and progressive dementia. The duration of Alzheimer’s disease-related dementia makes Alzheimer’s disease particularly pernicious; exacerbating the suffering of patients who live for nearly a decade as their brain matter slowly and irreversibly dies, and the suffering of family members and caregivers who helplessly stand by. The long duration also exacts a tremendous economic impact, which, in 2020 will amount to some $305 billion in the United States alone. Numerous therapies have been tested in clinical trials, yet as of today there is no treatment to effectively cure, or even slow the progression of Alzheimer’s disease, leaving a great unmet medical need. The accumulation of fibrillar aggregates -- extracellular plaques of Amyloid beta and intraneuronal tangles of tau -- are the defining characteristics of Alzheimer’s disease. However, with imaging and neuropathological studies overwhelmingly showing that plaque density correlates poorly with cognitive decline along with recent failures of drug development targeting Amyloid-beta plaques , the field is now shifting very quickly to focus on tau. Antibodies targeted against tau are now being evaluated in clinical trials; however, they face challenges in their ability to enter the brain and gain access into the neurons where aggregation takes place. Conversely, small molecules that can target aggregated tau directly within the neurons have been a great challenge to develop because of the difficulties in establishing a specific and well-defined binding site on the tau aggregates, and hence a clear mechanism of action. For the first time, a clear binding site has been described on AD-tau fibrils using cryoEM. It has been shown that the EGCG molecule bound to that site can disaggregate those fibrils with a structural explanation of this activity. Based on those preliminary studies, the proposed project encompasses a strategy in which ADRx will use the defined EGCG pharmacophore and expand the chemical matter screened against that entity first through in silico methods and then through experimental evaluation of hits. Our goal is to emerge from Phase 1 studies with structures of molecular complexes of AD-tau fibrils with 2-3 lead compounds with high potencies for AD-tau disaggregation, and promising drug-like properties (good metabolic stability and BBB penetration). In Phase 2 of the SBIR, we will refine these lead compounds and optimize potency and drug-likeness through a series of steps, using principles of medicinal chemistry and structure-based design, to show proof-of-efficacy in animal models of tauopathy. This proof-of-efficacy will provide the foundation for further optimization of these leads into drug candidates, and ultimately a translation of a structure-based AD-Tau disaggregant into the clinic.

抽象的 阿尔茨海默氏病是一种多因素疾病，其中许多机制在神经元死亡中达到顶峰， 脑萎缩和进行性痴呆。阿尔茨海默氏病的持续时间使 阿尔茨海默氏病特别有害；加剧生活近十年的患者的痛苦 当他们的大脑慢慢而不可逆转地死亡时，家庭成员和照顾者的苦难 无助地站在。漫长的持续时间还具有巨大的经济影响，这将在2020年将 仅在美国，就有约300亿美元。在临床试验中已经测试了许多疗法，但截至 如今，没有治疗方法可以有效治愈，甚至减慢了阿尔茨海默氏病的进展，留下了 巨大的未满足医疗需求。 原纤维聚集体的积累 - 淀粉样ββ的细胞外斑块和tau的神经元缠结 - 是阿尔茨海默氏病的定义特征。但是，随着成像和神经病理学研究 绝大多数表明斑块密度与认知能力下降以及最近失败的相关性很差 在针对淀粉样β斑块的药物开发中，该领域现在正在迅速转移以关注tau。 现在正在评估针对TAU的抗体。但是，他们面临着挑战 能够进入大脑并进入聚集的神经元。相反，小 可以直接在神经元内靶向tau的分子是发展的巨大挑战 因为很难在tau聚集体上建立特定且定义明确的结合位点，并且 因此，一种明确的作用机理。首次在Ad-Tau原纤维上描述了明确的结合位点 使用冷冻。已经表明，与该位点结合的EGCG分子可以将这些原纤维分解为 该活动的结构解释。基于这些初步研究，拟议的项目包括 ADRX将使用定义的EGCG药效团并扩展筛选的化学物质的策略 首先通过计算机方法对该实体进行对抗，然后通过对命中的实验评估。 我们的目标是从1阶段的研究中脱颖而出，该研究具有2-3 铅化合物具有高能量的AD-TAU分解和有前途的药物样特性（良好） 代谢稳定性和BBB渗透）。在SBIR的第2阶段中，我们将完善这些铅化合物，并 使用医学化学原理和 基于结构的设计，以显示tauopathy动物模型中的效率证明。这种效率证明将会 为这些导线进一步优化毒品候选者，并最终译为 基于结构的AD-TAU脱离诊所。