A discovery platform for novel bifunctional probes and molecular glues

新型双功能探针和分子胶的发现平台

• 批准号: 2601078
• 金额: --
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2601078
• 关键词: discovery; platform; novel; bifunctional; probes

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.

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点来实现其作用，大多数仅调节四种蛋白质类。大部分的蛋白质组目前被认为是“不可破坏的”，留下了一个明确的需要，新的模式，操纵蛋白质功能的机制，不依赖于紧密结合到一个传统的药物口袋。生物驱动的药理学已经成为影响蛋白质功能的革命性方法，例如双功能蛋白水解靶向嵌合体（PROTACS）和分子胶（2020年销售额超过100亿英镑）。该药物诱导感兴趣的靶蛋白（POI）和效应蛋白（通常是酶）之间的三元复合物形成，该效应蛋白对POI起催化作用以触发特定的细胞效应。效应招募药物调节蛋白质功能的潜力目前受到缺乏发现新的双功能/胶的通用方法的限制。该项目将开发一个平台，利用大规模编码分子库，新型共价配体筛选技术，合成化学和化学生物学从头发现这些实体。