Unlocking deubiquitinase probe discovery by high-throughput in-cell chemical proteomics

通过高通量细胞内化学蛋白质组学解锁去泛素酶探针发现

• 批准号: 2886820
• 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: 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=studentship-2886820
• 关键词: Unlocking; deubiquitinase; probe; discovery; throughput

The ubiquitin proteasome system (UPS) regulates myriad intracellular processes including protein turnover, through attachment of ubiquitin (Ub), a protein post-translational modification which tags proteins for degradation at the proteasome. More than 100 deubiquitinase (DUB) proteases catalyse Ub hydrolysis, thereby counteracting Ub ligase activity and regulating protein turnover. Altered DUB activity has been linked to a number of diseases and several DUBs are considered promising drug targets, with DUB inhibitors at various stages of preclinical or clinical development. However, target validation for DUB inhibitors has proven challenging, and there remains a pressing need for novel small molecule activity-based probes (ABPs) which can overcome the limitations of current generations of probes based on Ub which cannot be applied directly in intact cells or organisms. Building on recent advances in small molecule ABPs at Imperial (e.g. JACS 2020, 12020; J Med Chem 2020, 3756; ACS Chem Biol 2016, 3268; JACS 2021, 8911; JACS 2022, 22493) and the industry-leading discovery and screening platforms at Ubiquigent you will develop a new high-throughput chemical proteomic technology platform to comprehensively explore and interrogate DUB activity in intact cells. Working across a range of cancer cell line models, you will deliver the first in-cell screens of large compound libraries to identify new and selective DUB probes and inhibitors, revealing starting points for new classes of medicines. You will acquire a deep and wide range of expertise in this essential area for future drug discovery, including chemical probe design, chemical proteomics, machine learning and proteomics automation.

泛素蛋白酶体系统（UPS）通过附着泛素（UB）（ub）（一种蛋白质后的翻译后修饰）来调节包括蛋白质周转（UB）的无数细胞内过程，该蛋白质后修饰标记蛋白质在蛋白酶体上降解。超过100个去泛素酶（DUB）蛋白酶催化UB水解，从而抵消UB连接酶的活性并调节蛋白质更新。 DUB活性改变与多种疾病有关，几个配音被认为是有前途的药物靶标，在临床前或临床发育的各个阶段，DUB抑制剂。但是，对DUB抑制剂的目标验证已被证明具有挑战性，并且对新型小分子活性探针（ABP）仍然有着紧迫的需求，这些探针（ABP）可以克服基于UB的当前世代探针的局限有机体。基于帝国小分子ABP的最新进展（例如JACS 2020，12020; J Med Chem 2020，3756; ACS Chem Biol 2016，3268; JACS 2021，8911; JACS 2022，22493）和行业领域的发现和筛选平台在Ubigigent，您将开发一个新的高通量化学蛋白质组学技术平台，以全面探索和询问完整细胞中的DUB活动。您将在各种癌细胞系模型上工作，您将提供第一个大型复合文库的核心屏幕，以识别新的和选择性的DUB探针和抑制剂，从而揭示新类药物的起点。您将在这一必不可少的领域获得深厚的专业知识，以供未来的药物发现，包括化学探针设计，化学蛋白质组学，机器学习和蛋白质组学自动化。