A discovery platform for novel bifunctional probes and molecular glues

传统的小分子药物和化学探针通过化学计量结合其蛋白质靶标来实现其效果，大多数药物只调节四种蛋白质类别。目前大部分蛋白质组被认为是“不可用药的”，因此显然需要新的模式，通过不依赖于与传统可用药口袋的紧密结合的机制来操纵蛋白质的功能。效应器驱动的药理学已经成为影响蛋白质功能的一种革命性方法，例如双功能蛋白质降解靶向嵌合体(PROTACS)和分子胶(&gt；GB在2020年销售100亿美元)。该药物诱导靶蛋白(POI)和效应蛋白(通常是一种酶)之间形成三元复合体，效应蛋白催化作用于POI以触发特定的细胞效应。目前，由于缺乏发现新的双功能基团/胶的通用方法，招募效应器的药物调节蛋白质功能的潜力受到限制。该项目将利用大量编码分子库、新的共价配体筛选技术、合成化学和化学生物学，开发一个从头发现这些实体的平台。

Traditional small molecule drugs and chemical probes achieve their effect through stoichiometric binding of their protein targets, with the majority modulating just four protein classes. Much of the proteome is currently considered 'undruggable', leaving a clear need for new modalities that manipulate protein function through mechanisms which do not depend on tight binding to a conventional druggable pocket. Effector-driven pharmacology has emerged as a revolutionary approach to impact protein function, exemplified by bifunctional proteolysis-targeting chimeras (PROTACS) and molecular glues (>£10 billion sales in 2020). The drug induces ternary complex formation between a target protein of interest (POI) and an effector protein, often an enzyme, which acts catalytically on the POI to trigger a specific cellular effect. The potential of effector-recruiting drugs to modulate protein function is currently limited by the lack of general approaches to discover new bifunctionals/glues. This project will develop a platform for de novo discovery of these entities leveraging massive encoded molecular libraries, novel covalent ligand screening technologies, synthetic chemistry and chemical biology.