Small molecule Hsp90 inhibitors in AD treatment

描述（由申请人提供）：目前大部分阿尔茨海默病（AD）研究都集中在淀粉样蛋白通路的可能干预措施上，然而，这种集中的方法可能无法改善由于异常的tau磷酸化的结果。此外，阿尔茨海默病是一种复杂的异质性疾病，具有多种危险因素和多种症状。在后基因组时代，阿尔茨海默病的新分子靶点的鉴定可能提供了高特异性和降低全身毒性的理论希望，但这种高度集中的靶向方法面临着无法成功治疗复杂疾病的潜在危险，如阿尔茨海默病。相比之下，靶向Hsp90（一种允许非调控事件积累和进展的细胞机制）可能为阿尔茨海默病治疗提供更全面的方法。Hsp90抑制剂同时影响多种转化分子和途径的能力是靶向这种伴侣蛋白的独特和治疗上有吸引力的特征，这表明这些抑制剂可能比靶向单一信号分子的分子提供更广泛、更有效的抗神经退行性治疗，这是目前大多数药物发现工作的重点。此外，至少在癌症和神经退行性疾病中对Hsp90活性的需求明显增加，表明这种方法有可能成为一种可利用的治疗指标。我们的实验室率先发现和开发了合成Hsp90抑制剂，嘌呤支架抑制剂（pu类），并确定了具有良好血脑屏障通透性的衍生物。将这些分子应用于AD转基因小鼠，可诱导Hsp70产生，Hsp70是一种伴侣蛋白，能够将tau分割成有效的折叠途径，防止Abeta和tau聚集物的毒性，并调节异常神经元蛋白和减少毒性tau聚集物，但对小鼠没有毒性。基于这些数据，我们在此提出pu类Hsp90抑制剂代表了一种多角度的潜在新型治疗方法，可以延长受影响神经元的存活时间，并将U01申请中描述的研究重点放在将这些小分子Hsp90抑制剂作为潜在的新型阿尔茨海默病治疗药物应用于临床所需的步骤上。

DESCRIPTION (provided by applicant): The bulk of current Alzheimer's disease (AD) research is focused on possible interventions along the amyloid pathways however, this focused approach, may not ameliorate outcomes due to abnormal tau phosphorylation. In addition, AD is a complex and heterogeneous disease, with a diversity of risk factors and a multitude of symptoms. In the postgenomic era, identification of novel molecular targets for AD may offer the theoretical promise of great specificity coupled with reduced systemic toxicity, but this highly focused targeting approach faces the potential peril of being unable to deal successfully with a complex disease, such as AD. In contrast, targeting Hsp90, a cellular machinery that allows accumulation and progression of deregulated events, could provide a more comprehensive approach towards AD treatment. The ability of Hsp90 inhibitors to simultaneously affect multiple transforming molecules and pathways is a unique and therapeutically attractive feature of targeting this chaperone, suggesting that these inhibitors might provide a broader, more effective anti- neurodegenerative therapy than molecules targeting single signaling molecules that are the focus of most current drug discovery efforts. Moreover, the apparent increased requirement for Hsp90 activity in at least cancer and neurodegenerative diseases, suggests the real possibility of an exploitable therapeutic index for this approach. Our laboratory has pioneered the discovery and development of synthetic Hsp90 inhibitors, the purine-scaffold inhibitors (PU-class), and identified derivatives with favorable BBB-permeability profile. Administration of these molecules to AD transgenic mice resulted in induction of Hsp70, a chaperone able to partition tau into a productive folding pathway and to protect against Abeta and tau aggregate toxicity, and in modulation of aberrant neuronal proteins and a reduction in toxic tau aggregates, without toxicity to the mice. Based on these data, we propose here that the PU-class of Hsp90 inhibitors represents a multifaceted potential novel treatment to extend the survival of afflicted neurons, and focus the studies described in the U01 application on steps necessary for bringing these small molecule Hsp90 inhibitors to clinic as potential novel AD therapeutics. PUBLIC HEALTH RELEVANCE: Hsp90 inhibition offers a dual therapeutic approach in AD. First, it ameliorates protein misfolding by reduction of aberrant neuronal protein activity that leads to protein hyperphosphorylation and subsequent aggregation. Second, its benefit comes from induction of Hsp70, a chaperone able of redirecting neuronal aggregate formation, and of protective potential against both Abeta and tau aggregate toxicity.