Novel E3 ligase inhibitors for treatment of neurodegenerative disease

 描述（由申请人提供）：认知技能的进行性丧失是阿尔茨海默氏症（AD）等神经退行性疾病的标志，是医疗保健实施的主要挑战。目前还没有令人满意的治疗AD的方法，多种方法将是必要的成功的治疗管理。在这些方法中，有效的药物干预可以改善与AD和其他神经退行性疾病相关的认知缺陷。泛素E3连接酶是近年来发现的一类与多种病理学相关的分子靶点，包括神经元和其他细胞类型中的突触功能和对氧化应激反应的调节。IDOL是一种这样的连接酶;已知它使某些受体泛素化并促进其降解，所述受体包括ApoER 2和VLDLR，它们是脑中糖蛋白Reelin的主要受体。Reelin是记忆/认知的主要调节因子;通过ApoER 2和VLDLR介导的信号转导，Reelin结合增加长时程增强和突触可塑性。许多敲除和敲入研究以及小鼠模型表明，Reelin对学习和记忆产生积极影响;因此，Reelin信号传导的增强很可能在治疗AD和相关疾病的认知下降中提供益处。由于IDOL负责下调Reelin，因此在拟议项目中提出的治疗假设是，IDOL是用于开发将增强Reelin信号传导的小分子抑制剂的易处理的新靶标。预期IDOL的抑制剂增加脑中的ApoER 2和VLDLR水平并增强Reelin介导的突触可塑性。使用基于热位移的中试筛选，Progenra已经发现了几种IDOL抑制剂，初步数据表明这些IDOL抑制剂之一P0085255稳定ApoER 2。在拟议的项目中，将发现通过干扰IDOL和稳定ApoER 2和VLDLR来增强或刺激大脑中Reelin信号传导的新型小分子，并将其推向临床前开发。现有的抑制剂将通过化学优化进行开发，其他抑制剂将通过进一步筛选Progenra的整个小分子文库进行鉴定，并进行类似的优化。将使用生物化学、细胞和体内模型系统的组合评价选定的抑制剂稳定ApoER 2和VLDLR以及调节Reelin信号传导生物标志物的能力。在第二阶段，最有前途的化合物将使用适当的记忆和认知动物模型进行临床前开发。

 DESCRIPTION (provided by applicant): Progressive loss of cognitive skills, a hallmark of neurodegenerative diseases such as Alzheimer's (AD), represents a major challenge to healthcare implementation. No satisfactory treatments for AD currently exist, and multiple approaches will be necessary for successful therapeutic management. Among these approaches is effective pharmacologic intervention to ameliorate cognitive deficits associated with AD and other neurodegenerative diseases. Ubiquitin E3 ligases are a class of molecular target recently linked to a variety of pathologies, including synaptic function and regulation of te response to oxidative stress in neurons and other cell types. IDOL is one such ligase; it is known to ubiquitylate and promote the degradation of certain receptors, including ApoER2 and VLDLR, which are the major receptors for the glycoprotein Reelin in the brain. Reelin is a principal regulator of memory/cognition; via signal transduction mediated by ApoER2 and VLDLR, Reelin binding increases long term potentiation and synaptic plasticity. Numerous knock-out and knock-in studies as well as murine models show that Reelin exerts a positive effect on learning and memory; thus, augmentation of Reelin signaling is very likely to offer benefit in treating cognitive decline in AD and related diseases. Because IDOL is responsible for down-regulating Reelin, the therapeutic hypothesis addressed in the proposed project is that IDOL is a tractable novel target for developing small molecule inhibitors that will augment Reelin signaling. Inhibitors of IDOL are expected to increase ApoER2 and VLDLR levels in the brain and enhance Reelin mediated synaptic plasticity. Using a thermal shift based pilot screen, Progenra has discovered several IDOL inhibitors, and preliminary data demonstrate that one of these IDOL inhibitors, P0085255, stabilizes ApoER2. In the proposed project, novel small molecules that enhance or stimulate Reelin signaling in the brain by interfering with IDOL and stabilizing ApoER2 and VLDLR will be discovered and advanced toward pre-clinical development. Inhibitors already in hand will be developed by chemical optimization, and additional inhibitors will be identified by further screening of Progenra's entire small molecule library and optimized similarly. Selected inhibitors will be evaluated using a combination of biochemical, cellular, and in vivo model systems for their ability to stabilize ApoER2 and VLDLR as well as to modulate Reelin signaling biomarkers. In Phase II, the most promising compounds will advance into preclinical development using appropriate animal models for memory and cognition.