Mitophagy inhibitors for treatment of Alzheimer's Disease

 描述(申请人提供)：数百万人目前患有阿尔茨海默病(AD)；随着预期寿命的增加，这种疾病将变得越来越普遍。AD是由于海马区和内嗅皮层神经元的变性和死亡所致。终末期患者需要持续的护理，AD目前是美国第六大死因。目前还没有治愈方法；已批准的旨在改善认知和减缓病情发展的治疗方法主要集中在提高大脑中的乙酰胆碱水平。这种治疗有严重的副作用，只能在有限的时间内缓解AD症状，不能防止神经元死亡。因此，迫切需要确定通过作用于介导神经元死亡的靶点来防止AD进展的新型药物。线粒体就是这样一个靶子；AD相关神经元中功能失调的线粒体过多，降低了能量效率，并释放出导致神经元死亡的活性氧物种。功能失调的线粒体可通过磷酸化和泛素介导的自噬(有丝分裂)或自噬小体的降解来清除。泛素途径的组成部分包括结合酶parkin和去泛素酶USP30，前者用泛素标记有缺陷的线粒体进行移除，后者去结合泛素，防止有缺陷的线粒体被移除。正常情况下，AD患者清除有缺陷线粒体的能力被压倒，通过过度表达来取代parkin功能可以挽救体内的AD症状。此外，USP30基因敲除已被证明可以增强神经元中Parkin的活性和提高线粒体的完整性。这些发现导致假设USP30是开发用于治疗AD的小分子抑制剂的新靶点；USP30抑制剂有望防止吞噬细胞缺乏诱导的神经元死亡，从而阻止AD的进展。有人建议通过筛选不同的小分子集合来鉴定USP30的新调节子。将配置用于高通量筛选(HTS)的基于酶的USP30检测，并将筛选Progenra的220,000个化合物收藏。确认的命中将与相关类似物的子集一起重新排序，并在启动Hit to Lead优化程序之前针对一系列DUBS和其他蛋白酶进行分析。这一计划中最有希望的化合物将在吞丝分裂拯救的细胞模型中进行检验。在第二阶段，最有趣的化合物将通过相关的DMPK和其他细胞和动物模型研究进展到Hit-to-Lead药物化学优化。商业目标是一种治疗阿尔茨海默病的新药。

 DESCRIPTION (provided by applicant): Millions currently suffer from Alzheimer's disease (AD); as life expectancy increases, it will become increasingly widespread. AD results from the degeneration and death of neurons of the hippocampus and entorhinal cortex. End stage patients require continuous care, and AD is currently the sixth leading cause of death in the U.S. There is currently no cure; approved treatments, aimed at improving cognition and slowing progression, focus primarily on increasing the level of acetylcholine in the brain. Such treatments, which have serious side effects and relieve AD symptoms only for a limited time, cannot prevent neuronal death. Thus, an urgent need exists to identify novel agents that prevent AD progression by acting on targets that mediate neuronal death. The mitochondrion is such a target; excess dysfunctional mitochondria in AD-linked neurons lower energy efficiency and release reactive oxygen species contributing to neuronal death. The dysfunctional mitochondria are cleared by phosphorylation and ubiquitin-mediated autophagy (mitophagy), or degradation in auto phagosomes. The ubiquitin pathway component consists of the conjugating enzyme parkin, which tags defective mitochondria with ubiquitin for removal, and the deubiquitinating enzyme USP30, which deconjugates ubiquitin, preventing the removal of defective mitochondria. Normally, in AD patients the ability to clear defective mitochondria is overwhelmed, and replacement of parkin function by overexpression can rescue AD symptoms in vivo. Moreover, USP30 knockout has been shown to enhance parkin activity and increase mitochondrial integrity in neurons. These findings lead to the hypothesis that USP30 is a novel target for developing small molecule inhibitors for treatment of AD; USP30 inhibitors are expected to prevent mitophagy deficiency-induced neuronal death, thereby hindering progression of AD. It is proposed to identify novel modulators of USP30 by screening a diverse collection of small molecules. An enzymatic-based USP30 assay for high throughput screening (HTS) will be configured and Progenra's 220,000 compound collection will be screened. Confirmed hits will be reordered, along with a subset of related analogs, and profiled against a series of DUBs and other proteases before initiating a hit to lead optimization program. The most promising compounds from this program will be examined in cellular models of mitophagy rescue. In phase II, the most interesting compounds will be progressed to hit-to-lead medicinal chemistry optimization with associated DMPK and additional cellular and animal model studies. The commercial goal is a novel drug to treat AD.