Small molecule Parkin activators to treat Alzheimer's Disease

小分子 Parkin 激活剂治疗阿尔茨海默病

• 批准号: 9409673
• 负责人: Feng Wang
• 金额: $ 74.1万
• 依托单位: PROGENRA, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9409673
• 关键词: Acetylcholine; Address; Adverse effects; Affect; Age-Years; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; Animal Model; Appearance; Automobile Driving; Axon; Biological Assay; Brain; Brain region; Caring; Cause of Death; Cell Line; Cell model; Cells; Cessation of life; Chemicals; Crystallography; Cytosol; Deglutition; Dementia; Development; Disease; Disease Progression; Effectiveness; Emotional; Enzymes; Fluorescence Resonance Energy Transfer; Goals; Health; Hippocampus (Brain); In Vitro; Incidence; Lead; Learning; Life Expectancy; Link; Mediating; Memory; Memory Disorders; Mitochondria; Morbidity - disease rate; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurotransmitters; Onset of illness; PINK1 gene; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Phosphotransferases; Plant Roots; Point Mutation; Population; Production; Property; Reactive Oxygen Species; Symptoms; Testing; Therapeutic; Therapeutic Intervention; Time; Ubiquitin; United States; Vacuole; Walking; Work; age related; base; cost; drug discovery; efficacy study; entorhinal cortex; improved; in vivo; interest; mitochondrial dysfunction; mortality; mouse model; nervous system disorder; neuron loss; novel; novel therapeutics; overexpression; parkin gene/protein; preclinical development; prevent; small molecule; ubiquitin ligase; ubiquitin-protein ligase

Alzheimer’s disease (AD) affects an estimated 21-35 million worldwide; this number will double in the next decade. AD results from the degeneration and death of hippocampal and entorhinal cortex neurons in the brain, which are critical for learning and memory. Patients in end stage AD require round-the-clock care. Ultimately fatal with no cure available, AD is the sixth-leading cause of death in the US. Current therapies have serious side effects and cannot prevent neuronal death and disease progression, leading to efforts to identify novel therapeutics that stop AD progression. One target for such therapy is the mitochondrion. Mitochondrial damage and the appearance of autophagic vacuoles correlate with AD onset, and evidence suggests that mitophagy, a regulatory form of autophagic degradation mediated by the ubiquitin E3 ligase Parkin and the kinase PINK1, is overwhelmed and cannot prevent accumulation of damaged mitochondria in AD-affected neurons. Dysfunctional mitochondria in the axons of AD-linked neurons diminish energy production and release harmful reactive oxygen species; in these neurons, dysfunctional mitochondria accumulate due to inadequate mitophagy. Thus, therapeutic intervention in this compromised Parkin and PINK1-mediated mitophagy pathway is a promising strategy to improve mitochondrial integrity, preventing AD progression. Supporting this notion, overexpression of Parkin in an AD mouse model ameliorates AD-related symptoms, with improved mitochondrial integrity. Notably, the key factor of the mitophagy pathway, Parkin, is known to exist in an auto-inhibited ‘off’ state in cytosol, with very low basal level enzymatic activity. Its auto-inhibition is mediated by multiple intramolecular interactions, and point mutations that specifically disrupt these interactions activate Parkin activity and promote its translocation to dysfunctional mitochondria. The therapeutic hypothesis driving the current application is that small molecules that relieve auto-inhibitory interactions within Parkin can be used to selectively activate Parkin activity and facilitate mitochondrial health. Parkin activators are expected to prevent neuronal death induced by defective mitophagy, thereby hindering the progression of AD. It is proposed in this Phase II application to initiate preclinical development of selected small molecule activators of Parkin, identified in Phase I and shown to relieve auto-inhibition of Parkin, augmenting mitophagy in cells. This will be accomplished by performing lead optimization of selected Parkin activators, performing ADME/DMPK analyses (in vitro and in vivo) on compounds of interest, and demonstrating efficacy of optimized compounds in cellular and animal models of AD-related neurodegeneration. The ultimate commercial goal is the development of a novel small molecule agonist that can be used to treat neurological diseases with mitochondrial dysfunction.

据估计，全世界有2100-3500万人患有阿尔茨海默病；这一数字在下一年将翻一番 十年。AD是由于大脑中的海马神经元和内嗅皮层神经元的变性和死亡所致， 它们对学习和记忆至关重要。终末期AD患者需要全天候护理。最终 由于无法治愈，阿尔茨海默病是美国第六大致死原因。目前的治疗方法有严重的 副作用，无法阻止神经元死亡和疾病进展，导致努力确定新的 阻止阿尔茨海默病进展的治疗。这种疗法的一个目标是线粒体。线粒体损伤 自噬空泡的出现与AD的发病有关，有证据表明，有丝分裂是一种 泛素E3连接酶Parkin和激酶PINK1介导的自噬降解的调节形式是 不堪重负，无法阻止受AD影响的神经元中受损线粒体的积累。功能失调 AD相关神经元轴突中的线粒体减少能量产生并释放有害的活性氧 在这些神经元中，功能失调的线粒体由于吞噬作用不足而积累。因此， 对这种受损的Parkin和PINK1介导的有丝分裂吞噬通路的治疗干预是一种有希望的途径 改善线粒体完整性的策略，防止AD进展。支持这一概念，过度表达 在AD小鼠模型中使用Parkin可以改善AD相关症状，改善线粒体完整性。 值得注意的是，吞噬有丝分裂途径的关键因子Parkin已知存在于一种自动抑制的“关闭”状态 胞浆，具有很低的基础水平的酶活性。它的自身抑制是由多个分子内介导的 相互作用，以及特定破坏这些相互作用的点突变激活Parkin活性并促进 它被转移到功能失调的线粒体。推动当前应用的治疗假说是 解除帕金森病患者体内自我抑制相互作用的小分子可用于选择性激活帕金森病患者 活动和促进线粒体健康。帕金森激活剂有望防止由 有丝分裂缺陷，从而阻碍AD的进展。在此第二阶段申请中，建议启动 选定的帕金森病小分子激活剂的临床前开发，在I期确定并显示缓解 自动抑制Parkin，增强细胞中的有丝分裂吞噬。这将通过执行Lead来实现 优化选定的Parkin激活剂，对化合物进行ADME/DMPK分析(体外和体内) 有趣的是，优化的化合物在AD相关的细胞和动物模型中显示了有效性 神经退行性变。最终的商业目标是开发一种新型的小分子激动剂，它可以 用于治疗伴有线粒体功能障碍的神经系统疾病。