Developing a rule book for rational discovery of molecular glues for intractable targets

制定合理发现棘手目标分子胶的规则手册

• 批准号: EP/X025357/1
• 负责人: Julian Downward
• 金额: $ 526.58万
• 依托单位: The Francis Crick Institute
• 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%2FX025357%2F1
• 关键词: Developing; rule; book; rational; discovery

The UK has established world class capabilities in genomics and bioinformatics thanks to unique initiatives including Genomics England and the Wellcome Sanger Institute-led Open Targets platform and Cancer Dependency Map. These activities anchor multinational pharmaceutical companies in the UK, and underpin a highly successful and competitive biotech sector which raised a record £3 billion in new investment in 2021. While these UK-led programmes have contributed much to the understanding of the role the key players in driving many diseases, 85% of the proteomeis currently accessible through current small molecule strategies; referred to as the "undruggable" proteome.Conventional pharmacology approaches rely on small organic molecules which alter the activity of a given receptor or enzyme. Promising alternatives to these approaches are offered through molecules which reduce the abundance of aberrant target proteins, chemically tagging them and redirecting them for degradation through the cell's natural waste disposal system. In particular, a class of compounds, known as molecular glues, have recently been shown to enhance degradation of previously undruggable targets, potentially enhancing the therapeutically actionable space. Despite significant potential for impact, molecular glue discovery has so far been serendipitous, with a poor understanding of mechanism of action and the rules which govern their pharmacology, significantly reducing translational development in this area.Through this Prosperity Partnership, we propose developing an end-to-end approach to develop an understanding of the pre-requisites of molecular glues, using key biological pathways studied by Crick Researchers as the testing ground. Through this approach we will develop novel industrially relevant technology in areas hitherto untouched by conventional therapeutics, enhancing biological understanding and ultimately benefitting patients with difficult to treat diseases.

英国在基因组学和生物信息学方面建立了世界一流的能力，感谢您的独特举措，包括英格兰基因组学和惠康桑格研究所领导的开放目标平台和癌症依赖图。这些活动锚定了英国的跨国制药公司，并支撑了一个非常成功且竞争激烈的生物技术领域，该行业在2021年筹集了创纪录的30亿英镑的新投资。尽管这些以英国为主导的计划促进了对许多疾病的关键参与者的重要作用，但目前有85％的Proteomeis通过当前的小型小对象策略访问了许多疾病，被称为“不良”蛋白质组。规定的药理学方法依赖于改变给定受体或酶活性的小有机分子。这些方法的有希望的替代方法是通过分子提供的，这些分子可以减少异常靶蛋白的抽象，化学标记它们并通过细胞的自然废物处理系统进行降解。特别是，最近已证明一类称为分子胶的化合物可以增强以前不可能的靶标的降解，从而有可能增强治疗性可行的空间。尽管产生了巨大的影响，但迄今为止，分子胶水的发现一直是偶然的，对行动机制和控制其药理的规则的理解不足，大大降低了这一领域的转化发展。通过这种繁荣伙伴关系，我们提出了一种端到端的方法来开发一种对使用Mecular Glubue的研究者，通过对Crick进行了crick的研究，以开发一种对Crick acted Crick at ans Crick acting Crick进行了研究的方法。通过这种方法，我们将在迄今未经常规治疗剂所触及的领域开发新型的工业相关技术，增强生物学理解，并最终使患有难以治疗疾病的患者受益。