'Novel Shc Blockers as potential Alzheimer's Disease Therapeutics

抽象的。阿尔茨海默氏症(AD)目前影响着500多万美国人，是导致 成人中的痴呆症。虽然目前的药物略微延缓了症状，但还没有治愈或停止症状的药物 疾病的发展。NIA目前的一个重点是确定新的药物靶点，以解决对AD的复原力；此外， NIA有越来越多的观点认为，多靶点治疗可能是克服AD的必要手段。我们呈现的是 新药靶向Shc，最近被证明是从人类转化为 MCI至AD1，其活性在AD海马区2升高。此外，具有遗传降低Shc的PSAPP小鼠 蛋白质增加了认知功能、记忆力和存活率，同时也增加了斑块和缠结的负担-- 因此，Shc的减少代表了一种新的靶点，其减少使神经保护的“弹性”机制成为可能。 遗传Shc缺乏的小鼠也可以免受与年龄相关的脑血管功能障碍的保护。 因此，Shc活性的降低提高了在多种神经退行性疾病中的神经保护和弹性。至 尝试用小分子模拟遗传Shc减少所展示的神经保护益处，我们开始 通过改变用途的方法分离出6个具有Shc封闭活性的化学支架7。然后是一部新奇的3- 进行了三维支架搜索，在全新的支架上鉴定了400个新分子。这些 400个分子通过筛选范例被筛选为40个分子 在20个HTS测试中应用并测试它们，以授予神经细胞对淀粉样β蛋白的抵抗力，并选择了5 最具神经保护作用。对两个最具神经保护的人进行的PK实验显示，一个人的大脑外显率更高 分子。因此，Buto的目标是(1)确定该分子的最大耐受量(MTD)，2) 在氧化应激小鼠模型中测定大脑和血液中PBMC靶点的摄入量，以及3)确定 在5XFAD和ApoE4小鼠模型中的疗效。这些目标一旦实现，将决定在何种程度上 分子击中一个全新的和从未下药的AD靶点Shc，是可以接受的临床前 药物候选，并为Shc抑制剂在这一适应症中的进一步合作奠定了基础。

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.