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构成了许多神经退行性疾病的潜在共同病理机制。在tau蛋白病（包括阿尔茨海默病（AD）和额颞叶痴呆）的一组神经退行性疾病中，微管（MT）相关蛋白tau的过度磷酸化和聚集被认为通过毒性增加和/或功能丧失产生病理后果。我们实验室先前的研究表明，每周一次低剂量的脑渗透性 MT 稳定剂埃博霉素 D (epoD) 给予 tau 转基因 (Tg) 小鼠可改善轴突运输，减少轴突营养不良，增强认知能力并减少神经元病理。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 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性 MT 稳定剂的唯一例子。因此，显然需要开发和评估其他 CNS 活性 MT 稳定剂，以便确定替代的和可能改进的临床候选药物。为此，我们最近发现 dictyostatin 是一种有效的天然存在的 MT 稳定剂，在结构上与埃坡霉素无关，具有优异的脑渗透性和持久的药效作用。这些发现清楚地表明，Dicyostatin 可能是治疗 tau蛋白病的可行候选药物。因此，拟议研究计划的目标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数量的dictyostatin（目标1），然后在正常小鼠中进行耐受性/安全性研究（目标2）。目标 2 的结果将指导已建立的 tau Tg 小鼠模型研究的剂量和给药频率，其中将直接比较 dictyostatin 的功效与 epoD（目标 3）。此外，由于 dictyostatin 将于 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，因此我们将设计、合成和评估一系列可专利的 dictyostatin 前药，旨在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，以及 (b) 鉴定天然产物的一种或多种可申请专利的前药。这些研究将构成后续药物开发计划 (U01) 的基础，该计划的目标是将首选的 dictyostatin 前药推进到 IND 申请阶段。