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

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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.