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建立了世界级的能力，这要归功于独特的倡议，包括英国基因组学和惠康·桑格研究所领导的开放目标平台和癌症依赖地图。这些活动支撑着跨国制药公司在英国的地位，并为高度成功和竞争激烈的生物技术行业奠定了基础，该行业在2021年筹集了创纪录的30亿GB的新投资。虽然这些由英国领导的计划对理解导致许多疾病的关键参与者的作用做出了很大贡献，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赖于改变给定受体或酶的活性的小有机分子。通过减少异常目标蛋白的丰度的分子，对它们进行化学标记，并通过细胞的自然废物处理系统重新引导它们进行降解，可以提供这些方法的有前途的替代方案。特别是，一类被称为分子胶的化合物最近被证明可以促进以前无法下药的靶点的降解，潜在地增强了治疗上的可操作空间。尽管有巨大的潜在影响，但到目前为止，分子胶的发现是偶然的，对作用机制和支配其药理的规则缺乏了解，大大减少了这一领域的翻译开发。通过这种繁荣伙伴关系，我们建议开发一种端到端的方法来发展对分子胶先决条件的理解，使用克里克研究人员研究的关键生物学途径作为试验场。通过这种方法，我们将在传统疗法尚未触及的领域开发与工业相关的新技术，增强生物学理解，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.