KinoGlu: A Chemical Strategy to illuminate CNS Biology

KinoGlu：阐明中枢神经系统生物学的化学策略

• 批准号: EP/X020088/1
• 负责人: William Farnaby
• 金额: $ 54.41万
• 依托单位: University of Dundee
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FX020088%2F1
• 关键词: KinoGlu; Chemical; Strategy; illuminate; CNS

Many neurodegenerative illnesses have no effective treatments that address the cause of the disease. The chemistry currently used to treat these diseases accesses specific protein targets in the brain and typically, attempts to block them. These approaches have had a high clinical failure rate due to not working as hoped in humans. Developing new chemistry that can generate knowledge and treatment options that function differently are therefore needed. Targeted Protein Degradation is the method I will use to address this problem. This area of research is revolutionising chemical biology and drug discovery research. Cancer has been the early benefactor, but I wish to extend this to neurodegenerative and other Central Nervous System related diseases. Collectively, over 1 million people have Alzheimer's and Parkinson's Disease in the UK. Both diseases are progressive and have no cure. Generating chemical research tools that enable new treatment discoveries for these diseases would provide substantive societal benefit. This project will for the first time provide a rational method for designing and discovering molecules that can glue and degrade disease-causing proteins. This strategy will address critical issues relevant to this therapeutic area such as: - The specific protein expression patterns that may affect how Targeted Protein Degradation can be utilised to treat diseases in the brain. - Challenges associated with treatments reaching the brain - Selective chemical tools that can be used to robustly validate new therapeutic concepts To deliver my project I will make a toolbox of molecules that can bind to a group of therapeutically important proteins, Protein Kinases. These chemical tools will be able to glue disease causing protein kinases to other proteins that are part of the natural cell disposal system. The disease-causing proteins will be destroyed, returning the cell to health with no damage to healthy proteins. I will study how these tools behave in neuronal cells and use the findings as starting points to discover potent and selective kinase degrader glues. More broadly, this project will produce chemical tools and a design approach that will be useful to many scientists. They will provide knowledge about how proteins interact with each other, both in a cellular and an in vitro environment.

许多神经退行性疾病没有有效的治疗方法来解决疾病的原因。目前用于治疗这些疾病的化学物质进入大脑中的特定蛋白质靶点，通常试图阻止它们。这些方法由于在人类中不像所希望的那样工作而具有高临床失败率。因此，需要开发能够产生不同功能的知识和治疗选择的新化学品。靶向蛋白质降解是我将用来解决这个问题的方法。这一研究领域正在彻底改变化学生物学和药物发现研究。癌症是早期的受益者，但我希望将其扩展到神经退行性疾病和其他中枢神经系统相关疾病。总的来说，在英国有超过100万人患有阿尔茨海默氏症和帕金森氏症。这两种疾病都是渐进的，无法治愈。开发化学研究工具，使这些疾病的新的治疗方法的发现将提供实质性的社会效益。该项目将首次提供一种合理的方法来设计和发现能够粘合和降解致病蛋白质的分子。该策略将解决与该治疗领域相关的关键问题，例如：-可能影响靶向蛋白质降解如何用于治疗大脑疾病的特定蛋白质表达模式。 - 与到达大脑的治疗相关的挑战-选择性化学工具，可用于强有力地验证新的治疗概念为了实现我的项目，我将制作一个分子工具箱，这些分子可以与一组治疗上重要的蛋白质，蛋白激酶结合。这些化学工具将能够将导致疾病的蛋白激酶与其他蛋白质粘合在一起，这些蛋白质是自然细胞处理系统的一部分。致病蛋白质将被破坏，使细胞恢复健康，而不损害健康蛋白质。我将研究这些工具如何在神经元细胞中发挥作用，并将这些发现作为起点，以发现有效和选择性的激酶降解剂胶水。更广泛地说，这个项目将产生化学工具和设计方法，这将是有用的许多科学家。它们将提供有关蛋白质如何在细胞和体外环境中相互作用的知识。