Unlocking deubiquitinase (DUB) probe discovery by high-throughput incell chemical proteomics

This project is sponsored by the Institute of Chemical Biology EPSRC Centre for Doctoral Training and Ubiquigent

Supervisors:

Professor Ed Tate (Department of Chemistry, ICL)

Dr Sheelagh Frame (Ubiquigent Ltd)

Dr Joao Oliveira (Ubiquigent Ltd)

Dr Jack Houghton (Department of Chemistry, ICL)

Abstract:

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 (https://www.ubiquigent.com/platform) 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.

This project would suit a candidate interested in new approaches for drug discovery which apply chemistry to understand complex biological systems and cell biology. Prior experience in a multidisciplinary research environment, for example in chemical biology, would be an advantage. You will be mentored at Imperial by Prof Ed Tate and Dr Jack Houghton (http://www.imperial.ac.uk/tate-group/), and at Ubiquigent by Dr Sheelagh Frame (CSO) and Dr Joao Oliveira (Principal Scientist), in state-of-the-art chemical biology labs in the new £170M Molecular Sciences Research Hub at Imperial White City campus.

Prompt applications are strongly encouraged, candidates will be shortlisted for interview by mid-February 2023 

Eligibility:

The entry requirement is a degree in the physical sciences with a minimum 2.1 or above (or equivalent).

Chemistry, physics, mathematics and engineering graduates who wish to learn how to apply their physical sciences skills to biological problems. Students from biological or medicinal backgrounds are usually not eligible. If in doubt, please contact us

We are able to accept both ‘Home’ fee status and ‘Overseas’ fee status applicants for this project. Please see our Eligibility Criteria webpage for more detailed information.

About the ICB CDT

Successful applicants to this project will be part of 2023 entry cohort of the EPSRC CDT in Chemical Biology: Innovation for the Life Sciences. The aim of the ICB CDT, one of the longest standing CDTs in the UK, is to train students in the art of multidisciplinary Chemical Biology research, giving them the exciting opportunity to develop the next generation of molecular tools and technologies for making, measuring, modelling and manipulating molecular interactions in biological systems.

Applicants to this programme will enrol on a 1 year MRes in Chemical Biology and Bioentrepreneurship, followed by a 3 year PhD, building on the research project from the MRes. For further information, please see our studentship webpages.

Successful applicants, both Home and International, will be awarded a fully funded studentship. This includes:

• Annual National Minimum Doctoral Stipend, currently £17,668 + £2000 London allowance for 2022/23
• Annual Tuition fees at either the Home or Overseas fee rate for both the MRes and PhD years
• A Research Training Support Grant for laboratory consumable costs of £3,500 per year
• Funding to attend conferences
• Transferable skills training

How to apply

To apply for this project, please submit an application on the Imperial College Gateway (please see our How to Apply page for more detailed guidance).