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

英国在基因组学和生物信息学方面已经建立了世界一流的能力，这要归功于独特的举措，包括基因组学英格兰和威康桑格研究所领导的开放目标平台和癌症依赖图谱。这些活动为英国的跨国制药公司奠定了基础，并支撑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驱动许多疾病的关键角色做出了很大贡献，但目前85%的蛋白质组是通过当前的小分子策略获得的；被称为“不可药物”的蛋白质组。传统的药理学方法依靠小的有机分子来改变给定受体或酶的活性。有希望的替代方法是通过分子来减少异常靶蛋白的丰度，对它们进行化学标记，并通过细胞的自然废物处理系统将它们重新定向以进行降解。特别是，一类被称为分子胶的化合物，最近被证明可以增强以前不可药物靶标的降解，潜在地增加了治疗的可操作空间。尽管具有巨大的潜在影响，但迄今为止，分子胶的发现是偶然的，对其作用机制和控制其药理学的规则了解不足，大大减少了该领域的转化发展。通过这一繁荣伙伴关系，我们建议开发一种端到端方法，以克里克研究人员研究的关键生物途径作为试验场，来了解分子胶的先决条件。通过这种方法，我们将在传统疗法迄今未触及的领域开发新的工业相关技术，增强对生物学的理解，并最终使难以治疗的疾病患者受益。

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.