Preclinical Evaluation of a Novel Hsp90 inhibitor in Mutant Tau Mice

新型 Hsp90 抑制剂在 Tau 突变小鼠中的临床前评估

• 批准号: 7464465
• 负责人: LEONARD PETRUCELLI
• 金额: $ 16.73万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7464465
• 关键词: 17-(Allylamino)-17-demethoxygeldanamycin; Adopted; Affect; Affinity; Alzheimer' s Disease; Androgen Receptor; Binding; Biological Assay; Blood - brain barrier anatomy; Brain; Cells; Data; Development; Disease; Dose; Evaluation; Frontotemporal Dementia; Geldanamycin; Genes; Germ-Line Mutation; HSPB1 gene; Heat shock proteins; Heat-Shock Proteins 70; Heat-Shock Proteins 90; Heat-Shock Response; High Pressure Liquid Chromatography; Human; In Vitro; Longevity; Mediating; Memory; Memory Loss; Molecular Chaperones; Mus; Neurodegenerative Disorders; Neurons; Normal Cell; Parkinson Disease; Pathologic; Pathology; Personal Satisfaction; Phase; Process; Proteins; Screening procedure; Stimulus; Tauopathies; Tetracycline; Tetracyclines; Therapeutic; Time; Toxic effect; Transgenes; Transgenic Animals; Transgenic Organisms; Week; Western Blotting; brain tissue; cancer therapy; hyperphosphorylated tau; in vivo; inhibitor/antagonist; late disease onset; motor impairment; mouse model; multicatalytic endopeptidase complex; mutant; neoplastic cell; nervous system disorder; neuropathology; novel; pre-clinical; protein misfolding; response; spinal and bulbar muscular atrophy; tau Proteins; tau aggregation; tau mutation

DESCRIPTION (provided by applicant): Hereditary mutations within the MAPT (microtubule-associated protein tau) gene result in the pathologic and intra-neuronal aggregation of the tau protein that leads to frontotemporal dementia (FTD). The development of therapeutics for misfolded and abnormally processed (i.e. hyper-phosphorylated) tau species is necessary for sufferers of these autosomal tauopathic disorders and other neurological disorders which present with abnormal tau accumulation such as Alzheimer's disease (AD) and Parkinson's disease (PD). Molecular chaperones that are induced following a heat shock stimulus direct either the refolding of misfolded proteins and/or their targeting to the proteasome for degradation. Heat shock protein 90 (HSP90) inhibitors such as geldanamycin (GA) and its derivatives (17-allylamino-17-demethoxygeldanamycin; 17-AAG) can pharmacologically modulate chaperone levels and have recently been implicated for the treatment of cancer; sponsor NCI, Phase II) and mouse models of neurodegenerative disorders. In fact, Waza and colleagues recently showed that systemic administration of 17-AAG can markedly ameliorate motor impairments and life span in the spinal and bulbar muscular atrophy transgenic mouse model without detectable toxicity, by reducing amounts of monomeric and aggregated mutant androgen receptor. This study illustrates that Hsp90 inhibitors can be administrated chronically (20 weeks) and is well-tolerated. After screening a small panel of novel HSP90 inhibitors in a novel In-Cell Western assay that allows for direct intracellular quantitation of native and aberrant tau protein species, we identified a potent, blood brain barrier permeable HSP90 inhibitor (EC102) that significantly reduces abnormal tau species in vitro. In addition, we found that affected regions from human AD brain tissue have a significantly lower nanomolar binding affinity of Hsp90 for this novel inhibitor similar to tumor cells, while micromolar affinity was demonstrated in unaffected regions, comparable to normal cells. This suggests for the first time that in neurons, which progressively accumulate abnormal proteins in neurodegenerative disorders, and in this case AD, Hsp90 becomes engaged in active chaperoning and stabilization of these proteins and the Hsp90 adopts a novel high-affinity state. Thus these studies provide compelling evidence for the use of Hsp90 inhibitors to enhance Hsp90-mediated phospho-tau degradation in AD. We therefore propose that treatment with this compound may delay the progression of pathology and restore memory loss in mice that express a mutant form of human tau (P301L) driven by the tetracycline operator (rTg4510).

描述（由申请方提供）：MAPT（微管相关蛋白tau）基因内的遗传性突变导致tau蛋白的病理性和神经元内聚集，从而导致额颞叶痴呆（FTD）。开发用于错误折叠和异常加工（即过度磷酸化）的tau种类的治疗剂对于这些常染色体tau病变性病症和存在异常tau积累的其他神经病症如阿尔茨海默病（AD）和帕金森病（PD）的患者是必要的。在热休克刺激后诱导的分子伴侣指导错误折叠的蛋白质的重折叠和/或其靶向蛋白酶体进行降解。热休克蛋白90（HSP 90）抑制剂如格尔德霉素（GA）及其衍生物（17-烯丙基氨基-17-去甲氧基格尔德霉素; 17-AAG）可间接调节伴侣蛋白水平，并且最近已涉及治疗癌症（赞助NCI，II期）和神经变性疾病的小鼠模型。事实上，Waza及其同事最近表明，全身给予17-AAG可以显着改善脊髓和延髓肌萎缩转基因小鼠模型的运动障碍和寿命，而没有可检测到的毒性，通过减少单体和聚集的突变雄激素受体的量。这项研究表明，Hsp 90抑制剂可以长期给药（20周），并且耐受性良好。在新型In-Cell Western分析中筛选了一小组新型HSP 90抑制剂后，我们鉴定了一种有效的、可透过血脑屏障的HSP 90抑制剂（EC 102），其在体外显著减少异常tau蛋白种类，该分析允许直接细胞内定量天然和异常tau蛋白种类。此外，我们发现，从人类AD脑组织的受影响的地区有一个显着较低的热休克蛋白90的这种新的抑制剂类似于肿瘤细胞的纳摩尔结合亲和力，而微摩尔亲和力在未受影响的地区，证明与正常细胞。这首次表明，在神经退行性疾病中逐渐积累异常蛋白质的神经元中，在这种情况下，AD，Hsp 90参与这些蛋白质的活性伴侣和稳定，Hsp 90采用新的高亲和力状态。因此，这些研究为使用Hsp 90抑制剂增强AD中Hsp 90介导的磷酸化tau降解提供了令人信服的证据。因此，我们提出，用这种化合物治疗可能会延迟病理学的进展，并恢复小鼠的记忆丧失，这些小鼠表达由四环素操纵基因（rTg 4510）驱动的人tau（P301 L）突变形式。