'Novel Shc Blockers as potential Alzheimer's Disease Therapeutics

抽象的。阿尔茨海默病（AD）影响今天超过500万美国人，是最常见的原因， 成人痴呆症虽然目前的药物稍微延迟症状，没有药物存在治愈或停止 疾病进展。NIA目前的重点是确定新的药物靶点，解决AD的弹性问题;此外， 在NIA，多靶点治疗对于克服AD可能是必要的，这一观点越来越多。我们提出 该新药靶向Shc，其最近被证明是从人类转化中的主要弹性因子 MCI至AD 1，AD 2组活性升高。此外，遗传性Shc降低的PSAPP小鼠 蛋白质增加了认知功能、记忆力和存活率，但斑块和缠结的负担相同-- 因此，Shc的减少代表了一种新的靶点，其减少能够实现神经保护性的“恢复”机制3。 具有遗传性Shc缺陷的小鼠也被保护免于年龄相关的脑血管功能障碍4 ALS 5和MS 6， 因此，在多种神经退行性疾病中，Shc活性的降低增加了神经保护和恢复能力。到 为了用一种小分子来模拟遗传性Shc减少的神经保护作用，我们开始 用再利用方法分离6种具有Shc阻断活性的化学支架7。一本小说3- 进行三维支架搜索以鉴定在完全新颖的支架上的400个新分子。这些 400个分子已经通过文献中描述的筛选范例被筛选到40个分子的群体。 应用程序，并在20个HTS测定中测试它们，以赋予神经细胞对淀粉样蛋白β的抗性，并挑选了5个 最能保护神经对两种最具神经保护作用的药物进行PK实验，结果显示， 分子。因此，Buto的目的是（1）确定该分子的最大耐受剂量（MTD），2） 确定氧化应激小鼠模型中的脑和血液PBMC靶结合，以及3）确定 在5XFAD和ApoE 4小鼠模型中的有效性。这些目标一旦实现，将决定 分子击中一个完全新的和从未药物AD目标Shc，是可接受的临床前 药理学候选物，并为Shc抑制剂在该适应症中的进一步合作奠定基础。

Abstract. Alzheimer’s disease (AD) affects more than 5M Americans today, and is the most common cause of dementia in adults. While current medications slightly delay symptoms, no medications exist to cure or stop disease progression. A current focus at NIA is to identify novel drug targets, that address resilience to AD; also, there is an increasing perspective at NIA that Multi-target therapy may be necessary to overcome AD. We present the novel drug target Shc, which was recently shown to be a major resilience factor in conversion from human MCI to AD1, and whose activity rises in AD hippocampus2. Also, PSAPP mice with genetically decreased Shc protein had increased cognitive function and memory and survival, with the same burden of plaques and tangles-- thus Shc reduction represents a novel target whose reduction enables a neuroprotective 'resilience' mechanism3. Mice with genetic Shc deficiency are also protected from age related cerebrovascular dysfunction4 ALS5 and MS6, so reduction of Shc activity increases neuroprotection and resilience in multiple neurodegenerative conditions. To try to mimic the demonstrated neuroprotective benefit of genetic Shc reduction with a small molecule, we started with a repurposing approach to isolate 6 chemical scaffolds with Shc blocking activity7. Then a novel 3- dimensional scaffold search was carried out to identify 400 new molecules on completely novel scaffolds. These 400 have been winnowed down to a flock of 40 molecules through screening paradigms described in the application and tested them in 20 HTS assays to confer neural cell resistance to amyloid beta and picked the 5 most neuroprotective. PK experiments on the 2 most neuro-protective revealed a better brain penetrance of one molecule. Thus Buto's Aims are (1) to identify the Maximum Tolerated Dose (MTD) of this molecule, 2) to determine Brain and Blood PBMC target engagement in a mouse model of oxidative stress, and 3) to determine efficacy in the 5XFAD and ApoE4 mouse model. These Aims, once achieved, will determine the extent to which molecules that hit a completely novel and never-drugged AD target Shc, are acceptable pre-clinical pharmacological candidates, and set the stage for further partnering of Shc inhibitors in this indication.