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.

摘要 阿尔茨海默病是一种多因素疾病，其中许多机制最终导致神经元死亡， 脑萎缩和进行性痴呆阿尔茨海默病相关痴呆的持续时间使得 阿尔茨海默氏病尤其有害;加剧了患者的痛苦谁住了近十年 因为他们的大脑物质缓慢而不可逆转地死亡，家庭成员和照顾者的痛苦， 无助地站在一旁。持续时间长也会带来巨大的经济影响，到2020年， 仅在美国就高达3050亿美元。许多疗法已经在临床试验中进行了测试，但截至 今天，没有有效的治疗方法来治愈，甚至减缓阿尔茨海默病的进展， 巨大的未满足的医疗需求 纤维聚集体的积累--β淀粉样蛋白的细胞外斑块和tau蛋白的神经元内缠结 --是阿尔茨海默病的典型特征。然而，通过影像学和神经病理学研究， 压倒性地显示，斑块密度与认知能力下降沿着以及近期的失败相关性很低 随着针对β淀粉样蛋白斑块的药物开发的不断深入，该领域现在正迅速转向关注tau蛋白。 靶向tau的抗体现在正在临床试验中进行评估;然而，它们在其应用中面临挑战。 进入大脑并进入聚集发生的神经元的能力。相反，小 能够直接靶向神经元内聚集的tau蛋白的分子一直是开发的巨大挑战 由于在tau聚集体上建立特异性和明确的结合位点的困难， 因此有明确作用机制。这是第一次，一个明确的结合位点已被描述的AD-tau纤维 使用冷冻电镜。已经表明，结合到该位点的EGCG分子可以使那些原纤维解聚， 这一活动的结构性解释。根据这些初步研究，拟议项目包括 ADRx将使用定义的EGCG药效团并扩展筛选的化学物质的策略 首先通过计算机模拟方法，然后通过命中的实验评估。 我们的目标是从1期研究中获得AD-tau原纤维与2-3 具有高效力的AD-tau解聚和有希望的药物样性质的先导化合物（良好的 代谢稳定性和BBB渗透）。在SBIR的第二阶段，我们将改进这些先导化合物， 通过一系列步骤优化效力和药物相似性，使用药物化学原理， 基于结构的设计，在tau蛋白病动物模型中显示功效证明。这一有效性证明将 为进一步优化这些先导化合物成为候选药物提供了基础，并最终转化为 一种基于结构的AD-Tau解聚剂。