'Novel Shc Blockers as potential Alzheimer's Disease Therapeutics

“新型 Shc 阻滞剂作为潜在的阿尔茨海默病治疗药物

基本信息

批准号：
10611613
负责人：
Gino A Cortopassi
金额：
$ 32.94万
依托单位：
BUTO CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2024-08-31
项目状态：
已结题

项目摘要

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.

摘要：阿尔茨海默病 (AD) 影响着超过 500 万美国人，并且是最常见的病因。虽然目前的药物可以稍微延缓成人痴呆症的症状，但尚无药物可以治愈或停止。 NIA 目前的重点是确定新的药物靶点，以解决 AD 的恢复问题； NIA 越来越多的观点认为，多靶点治疗可能是克服 AD 所必需的。新的药物靶标 Shc，最近被证明是从人类转化的主要恢复因素 MCI 至 AD1，其 AD 海马体活性升高。此外，Shc 基因降低的 PSAPP 小鼠。蛋白质增强了认知功能、记忆力和生存率，同时也带来了相同的斑块和缠结负担—— 因此，Shc 的减少代表了一个新的目标，其减少可以实现神经保护“弹性”机制3。具有遗传性 Shc 缺陷的小鼠也可以免受年龄相关的脑血管功能障碍4 ALS5 和 MS6，因此，Shc 活性的减少可以增加多种神经退行性疾病的神经保护和恢复能力。尝试用小分子模仿已证实的基因 Shc 减少的神经保护益处，我们开始通过重新利用的方法分离出 6 种具有 Shc 阻断活性的化学支架7。进行了三维支架搜索，以在全新的支架上识别出 400 个新分子。通过 400 中描述的筛选范例，已将 400 个分子分解为 40 个分子群。应用并在 20 项 HTS 测定中对其进行测试，以赋予神经细胞对淀粉样蛋白 β 的抵抗力，并选出 5 种对 2 种最具神经保护作用的 PK 实验显示，其中一种具有更好的脑外显率。因此，Buto 的目标是 (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大脑和血液 PBMC 靶点的参与情况，以及 3) 确定这些目标一旦实现，将决定其在 5XFAD 和 ApoE4 小鼠模型中的功效。击中完全新颖且从未使用药物的 AD 靶标 Shc 的分子是可接受的临床前治疗药理学候选药物，并为 Shc 抑制剂在该适应症方面的进一步合作奠定了基础。