Dictyostatin and related prodrugs as candidates for tauopathy treatment

Dictyostatin 和相关前药作为 tau 蛋白病治疗的候选药物

• 批准号: 8821175
• 负责人: Amos B Smith
• 金额: $ 40万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8821175
• 关键词: Alzheimer' s Disease; Animal Model; Attenuated; Axonal Transport; Binding; Biological Factors; Brain; Cessation of life; Clinical; Clinical Trials; Cognitive; Counseling; Dementia; Deposition; Development; Development Plans; Dose; Drug Kinetics; Epothilones; Evaluation; Exhibits; Financial compensation; Frequencies; Frontotemporal Dementia; Future; Grant; Hippocampus (Brain); Human; In Vitro; Laboratories; Lead; Legal; Letters; Microtubule stabilizing agent; Microtubule-Associated Proteins; Microtubules; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuronal Dysfunction; Neurons; Neuropil Threads; Pathology; Patients; Penetration; Performance; Peripheral; Pharmaceutical Preparations; Pharmacodynamics; Phase; Plasma; Prodrugs; Property; Public Domains; Reporting; Research; Safety; Schedule; Series; Solubility; Staging; Tauopathies; Therapeutic; Transgenic Animals; Transgenic Mice; United States National Institutes of Health; analog; base; commercialization; comparative efficacy; design; dictyostatin; drug candidate; drug development; epothilone D; improved; in vivo; loss of function; mouse model; neuron loss; prevent; programs; protein aggregation; protein misfolding; public health relevance; safety study; tau Proteins; tau aggregation; tau function; treatment strategy

 DESCRIPTION (provided by applicant): Protein misfolding and aggregation comprise the underlying common pathological mechanism of many neurodegenerative disorders. In the case of tauopathies, a group of neurodegenerative diseases which include Alzheimer's disease (AD) and frontotemporal dementias, the hyperphosphorylation and aggregation of the microtubule (MT)-associated protein tau is believed to have pathological consequences via toxic gain and/or loss of functions. Previous studies from our laboratories have demonstrated that administration of low once- weekly doses of the brain-penetrant MT-stabilizing agent, epothilone D (epoD), to tau transgenic (Tg) mice resulted in improved axonal transport, reduced axonal dystrophy, enhanced cognitive performance and decreased neuronal pathology. These results thus suggest that compensation for the loss of tau MT-stabilizing function may be a viable therapeutic strategy for the treatment of tauopathies. However, epoD is the only example of a brain-penetrant MT-stabilizing agent that to date has undergone in vivo efficacy studies in tau Tg animal models. As a result, the development and evaluation of additional CNS-active MT-stabilizing agents is clearly desirable so as to identify alternative and potentially improved clinical candidates. Towards this end, we have recently discovered that dictyostatin, a potent naturally occurring MT-stabilizing agent that is structurally unrelated to the epothilones, exhibit excellent brain penetration and long-lasting pharmacodynamic effects. These findings clearly suggest that dictyostatin may be a viable drug candidate for the treatment of tauopathies. Thus, the objectives of the proposed research plan are to synthesize quantities of dictyostatin (Aim 1) that would be sufficient to fully characterize both pharmacokinetics and pharmacodynamics of this natural product, followed by tolerability/safety studies in normal mice (Aim 2). The results o Aim 2 will guide the dose amount and dosing frequency for studies in an established tau Tg mouse model, in which the efficacy of dictyostatin will be directly compared to epoD (Aim 3). In addition, since dictyostatin will become a public domain compound in April, 2014, thereby hampering future development and commercialization, we will design, synthesize and evaluate a focused series of patentable dictyostatin prodrugs that are designed to release the active natural product in plasma upon administration (Aim 4). If successful, the proposed research plan will: (a) validate dictyostatin as a drug candidate for the treatment of tauopathies and (b) identiy one or more patentable prodrugs of the natural product. These studies will form the basis of a subsequent drug-development plan (U01) in which the objective will be to advance a preferred dictyostatin prodrug to the point of filing of an IND.

 描述（由申请人提供）： 蛋白质错误折叠和聚集包括许多神经退行性疾病的潜在共同病理机制。在tau蛋白病（一组神经变性疾病，包括阿尔茨海默病（AD）和额颞痴呆）的情况下，微管（MT）相关蛋白tau的过度磷酸化和聚集被认为通过毒性获得和/或功能丧失而具有病理后果。来自我们实验室的先前研究已经证明，向tau转基因（Tg）小鼠施用每周一次低剂量的脑渗透MT稳定剂埃坡霉素D（epoD）导致轴突运输改善、轴突营养不良减少、认知表现增强和神经元病理减少。因此，这些结果表明，补偿tau MT稳定功能的丧失可能是治疗tau蛋白病的可行治疗策略。然而，epoD是迄今为止在tau Tg动物模型中进行体内功效研究的脑渗透MT稳定剂的唯一实例。因此，开发和评价额外的CNS活性MT稳定剂显然是可取的，以确定替代的和潜在的改进的临床候选药物。为此，我们最近发现，dictyostatin，一种有效的天然存在的MT稳定剂，其结构上与埃博霉素无关，表现出优异的脑渗透性和持久的药效学作用。这些发现清楚地表明，网丝抑素可能是一个可行的候选药物治疗tau蛋白病。因此，拟定研究计划的目的是合成足以充分表征这种天然产物的药代动力学和药效学的大量的网壳抑素（目的1），然后在正常小鼠中进行耐受性/安全性研究（目的2）。目标2的结果将指导在已建立的tau Tg小鼠模型中进行的研究的剂量和给药频率，其中将直接比较网壳抑素与epoD的疗效（目标3）。此外，由于dictyostatin将在2014年4月成为公共领域化合物，从而阻碍未来的开发和商业化，我们将设计、合成和评估一系列集中的可专利的dictyostatin前药，这些前药被设计为在给药后在血浆中释放活性天然产物（目标4）。如果成功，拟议的研究计划将：（a）验证dictyostatin作为治疗tau蛋白病的候选药物和（B）确定一个或多个可申请专利的天然产物前药。这些研究将构成后续药物开发计划（U01）的基础，其中的目标是将优选的dictyostatin前药推进到IND备案的时间点。