Small molecule Hsp90 inhibitors in AD treatment

描述（由申请人提供）：目前阿尔茨海默病（AD）研究的大部分集中在淀粉样蛋白通路上的可能干预沿着，然而，这种集中的方法可能不会改善由于异常tau磷酸化导致的结果。此外，AD是一种复杂且异质性的疾病，具有多种风险因素和多种症状。在后基因组时代，识别AD的新分子靶点可能提供理论上的承诺，即具有更高的特异性，同时降低全身毒性，但这种高度集中的靶向方法面临着无法成功处理复杂疾病（如AD）的潜在危险。相比之下，靶向Hsp90，一种允许失调事件积累和进展的细胞机制，可以提供更全面的AD治疗方法。Hsp90抑制剂同时影响多个转化分子和途径的能力是靶向该分子伴侣的独特和治疗上有吸引力的特征，表明这些抑制剂可能提供比靶向单一信号传导分子的分子更广泛、更有效的抗神经变性疗法，所述单一信号传导分子是大多数当前药物发现努力的焦点。此外，至少在癌症和神经变性疾病中对Hsp90活性的明显增加的需求表明了这种方法的可利用的治疗指数的真实的可能性。我们的实验室率先发现和开发了合成的Hsp90抑制剂，嘌呤支架抑制剂（PU类），并鉴定了具有良好BBB渗透性的衍生物。向AD转基因小鼠施用这些分子导致Hsp70的诱导，Hsp70是一种能够将tau分配到生产性折叠途径中并保护免受Abeta和tau聚集体毒性的分子伴侣，并且导致异常神经元蛋白的调节和毒性tau聚集体的减少，而对小鼠没有毒性。基于这些数据，我们在此提出，PU类Hsp90抑制剂代表了延长受累神经元存活的多方面潜在新型治疗，并将U01申请中描述的研究集中在将这些小分子Hsp90抑制剂作为潜在新型AD治疗剂带入临床所需的步骤上。 公共卫生相关性：Hsp90抑制提供了AD的双重治疗方法。首先，它通过减少异常神经元蛋白活性来改善蛋白质错误折叠，异常神经元蛋白活性导致蛋白质过度磷酸化和随后的聚集。第二，其益处来自Hsp70的诱导，Hsp70是一种能够重定向神经元聚集体形成的分子伴侣，并且具有针对Abeta和tau聚集体毒性的保护潜力。

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.