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

摘要 阿尔茨海默病是一种多因素疾病，其多种机制最终导致神经元死亡， 脑萎缩和进行性痴呆症。阿尔茨海默病相关痴呆症的持续时间使 阿尔茨海默病尤其有害；加剧了活了近十年的患者的痛苦 由于他们的大脑物质缓慢而不可逆转地死亡，以及家庭成员和照顾者的痛苦 无助地袖手旁观。持续时间长还会带来巨大的经济影响，2020年将达到 仅在美国就达到了约3050亿美元。许多治疗方法已经在临床试验中进行了测试，但截至 今天，没有有效治愈甚至减缓阿尔茨海默病进展的治疗方法，留下了 巨大的未得到满足的医疗需求。 纤维聚集--β淀粉样蛋白的细胞外斑块和tau蛋白的神经元内缠结 -是阿尔茨海默病的定义特征。然而，随着影像和神经病理学的研究 压倒性地表明斑块密度与认知能力下降以及最近的失败之间的相关性很差 在针对淀粉样β蛋白斑块的药物开发方面，该领域现在正在非常迅速地转移到专注于tau。 针对tau的抗体目前正在临床试验中进行评估；然而，它们在 进入大脑并进入发生聚集的神经元的能力。相反，小的 可以直接靶向神经元内聚集的tau的分子一直是一个巨大的挑战。 由于在tau聚集体上建立特定和明确定义的结合部位的困难，以及 因此，有一个明确的行动机制。首次在AD-tau纤维上描述了一个清晰的结合部位 使用的是冷冻EM。已经证明，与该部位结合的EGCG分子可以通过 对这一活动的结构性解释。根据这些初步研究，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，然后通过对HITS的实验评估。 我们的目标是从第一阶段的研究中发现AD-tau纤维与2-3的分子络合物的结构 具有AD-tau解聚的高势的先导化合物，以及有希望的类药物特性(良好 代谢稳定性和血脑屏障渗透率)。在SBIR的第二阶段，我们将提炼这些先导化合物和 通过一系列步骤，利用药物化学和生物化学的原理，优化药效和药物的相似性 以结构为基础的设计，以证明疗效在动物模型的直立位。这一有效性证明将 为进一步将这些线索优化为候选药物并最终翻译成 一种基于结构的AD-Tau解聚剂进入临床。

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.