Small molecule Parkin activators to treat Alzheimer's Disease

小分子 Parkin 激活剂治疗阿尔茨海默病

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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，全球有 21-3500 万人患有阿尔茨海默氏病 (AD)；未来这个数字将增加一倍； AD是大脑海马和内嗅皮层神经元退化和死亡的结果，这对学习和记忆至关重要。AD 末期患者最终需要全天候护理。 AD 是致命的且无法治愈，是美国第六大死因，目前的治疗方法有严重的副作用。副作用并且不能阻止神经死亡和疾病进展，导致人们努力寻找新的治疗方法阻止 AD 进展的疗法之一是线粒体损伤。自噬空泡的出现与 AD 发病相关，有证据表明线粒体自噬是一种由泛素 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。 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物种；在这些神经元中，功能失调的线粒体由于线粒体自噬不足而积累。对这种受损的 Parkin 和 PINK1 介导的线粒体自噬途径进行治疗干预是一种有前途的方法改善线粒体完整性、防止 AD 进展的策略支持了这一观点，即过度表达。 Parkin 在 AD 小鼠模型中的作用可改善 AD 相关症状，并改善线粒体完整性。值得注意的是，已知线粒体自噬途径的关键因子 Parkin 在体内以自动抑制“关闭”状态存在。胞质溶胶，具有非常低的基础水平酶活性，其自身抑制是由多个分子内介导的。相互作用，以及专门破坏这些相互作用的点突变激活 Parkin 活性并促进其易位至功能失调的线粒体。推动当前应用的治疗假设是：缓解 Parkin 内自抑制相互作用的小分子可用于选择性激活 Parkin 活性并促进线粒体健康，预计可以预防由帕金蛋白引起的神经元死亡。有缺陷的线粒体自噬，阻碍AD的进展，从而启动II期应用。选定的帕金小分子激活剂的临床前开发，在第一阶段鉴定并显示可以缓解 Parkin 的自动抑制，增强细胞中的线粒体自噬，这将通过铅来实现。优化选定的 Parkin 激活剂，对化合物进行 ADME/DMPK 分析（体外和体内）感兴趣的，并证明优化化合物在 AD 相关细胞和动物模型中的功效最终的商业目标是开发一种新型小分子激动剂。用于治疗线粒体功能障碍的神经系统疾病。