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

泛素蛋白酶体系统(UPS)通过连接泛素(Ub)调节多种细胞内过程，包括蛋白质周转。Ub是一种蛋白质翻译后修饰，标记蛋白质在蛋白酶体上的降解。超过100种脱泛素酶(DUB)酶催化Ub水解酶，从而抵消Ub连接酶的活性，调节蛋白质的周转。DUB活性的改变与许多疾病有关，几种DUB被认为是有希望的药物靶点，DUB抑制剂处于临床前或临床开发的不同阶段。然而，DUB抑制剂的靶向验证具有挑战性，迫切需要新型的基于小分子活性的探针(ABPs)来克服当前几代基于Ub的探针不能直接应用于完整细胞或生物体的局限性。在Imperial的小分子ABPs(如JACS2020,12020；J Med Chem 2020,3756；ACS Chem Biol2016,3268；JACS2021,8911；JACS2022,22493)和Ubiquigent行业领先的发现和筛选平台的最新进展基础上，您将开发一个新的高通量化学蛋白质组技术平台，以全面探索和询问完整细胞中的DuB活性。在一系列癌症细胞系模型中工作，您将提供大型化合物文库的第一个细胞内筛查，以识别新的和选择性的Dub探针和抑制剂，揭示新类别药物的起点。你将在这一未来药物发现的关键领域获得广泛而深入的专业知识，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。

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.