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.

英国已经建立了世界一流的基因组学和生物信息学能力，这要归功于包括英国基因组学和威康桑格研究所领导的开放目标平台和癌症依赖地图在内的独特举措。这些活动为英国的跨国制药公司提供了锚，并巩固了一个非常成功和具有竞争力的生物技术行业，该行业在2021年筹集了创纪录的30亿英镑新投资。虽然这些由英国主导的项目对理解在驱动许多疾病中的关键角色做出了很大贡献，但目前85%的蛋白质组可通过当前的小分子策略获得;被称为“不可药物化的”蛋白质组。这些方法的有希望的替代方案是通过减少异常靶蛋白丰度的分子提供的，化学标记它们并通过细胞的天然废物处理系统将它们重定向降解。特别是，一类被称为分子胶的化合物最近已被证明可以增强以前不可用的靶标的降解，从而潜在地增强治疗上可操作的空间。尽管有巨大的影响潜力，但迄今为止，分子胶的发现都是偶然的，对作用机制和控制其药理学的规则缺乏了解，大大减少了这一领域的转化发展。通过这个繁荣伙伴关系，我们建议开发一种端到端的方法来了解分子胶的前体，使用克里克研究人员研究的关键生物途径作为试验场。通过这种方法，我们将在传统疗法尚未触及的领域开发新的工业相关技术，增强生物学理解，并最终使难以治疗的疾病患者受益。