Tailored targeted protein degradation therapy by the identification of cancer-cell specific ubiquitin E3 ligases

Targeted protein degradation (TPD) (e.g. PROTAC) is emerging as a revolutionary therapeutic modality. TPD involves rewiring the substrate specificity of a ubiquitin E3 ligase with bifunctional small molecules that engage both the E3 and the desired substrate. TPD of oncoproteins has been shown to have great promise for cancer treatment. However, in addition to driving cancer, oncogenic proteins can also be essential for healthy cells. This limits the utility of existing systems because some oncogenic proteins cannot be targeted without serious on-target side effects. In principle, these side effects can be mitigated by exploiting biological specificity through the development of a TPD system that rewires an E3 whose activity is spatially restricted to diseased cells. Our lab has developed a suite of semisynthetic protein sensors that can survey different cell types for E3 activity (Pao et al. Nature 2018; Mathur et al. Cell Chem. Biol 2020). This project will use this technology to establish E3 ligase activity maps for cancer and control cell lines. Once cancer-specific E3 ligases have been identified and validated, model systems will be used to assess their utility in tailored TPD as a therapeutic strategy for treating cancers which are currently intractable. This project is industrially funded by a pharmaceutical partner as part of the MRC PPU’s longstanding Division of Signal Transduction Therapy collaboration.

Motivated candidates should ideally have recently carried out a PhD working in the area of cancer biology with experience in proteomics being desirable. The position will be a fantastic opportunity for the successful candidate to broaden their skill-set using state-of-the-art, interdisciplinary techniques. They will join an international team in an exciting and interactive environment, equipped to the very highest standards, and with generous consumable support.

Candidate Requirements:

• PhD, with outstanding academic track record and at least one first authored publication in an internationally recognised journal.
• Capable of working in a team, but able to plan and work independently.
• Excellent communication skills and knowledge of the English language.

The position is available immediately and is open to both international and UK applicants. The contract is fixed-term for 24 months.

The appointment will be made on the University of Dundee Grade 7 salary scale, with the initial placement being dependent on achievements and experience.

Appointment as a Postdoctoral Research Assistant on the Grade 7 salary scale is dependent upon you having been awarded a PhD. An appointment may be considered if you are shortly expected to be awarded a PhD. The initial appointment would be made as a Research Assistant on the Training Grade 7 salary scale (Spinal Point 25 - 28 £29,176 - £31,866).

For further information about this position please contact Satpal Virdee at s.s.virdee@dundee.ac.uk. To find out more about MRC PPU please visit http://www.ppu.mrc.ac.uk.

To apply online please visit: www.dundee.ac.uk/jobs

MRC Protein Phosphorylation and Ubiquitylation Unit (PPU):

The MRC-PPU is one of the world’s most renowned centres for research on protein phosphorylation and ubiquitylation (http://www.ppu.mrc.ac.uk) and has an exciting and collaborative research environment, equipped to the highest international standards. The major aims of the MRC-PPU are to advance understanding of the role of protein phosphorylation and ubiquitylation in cell regulation and human disease; to facilitate the development of drugs to treat diseases caused by abnormalities in phosphorylation; and to generate reagents and improve technologies. Another key remit of the MRC-PPU is to train the next generation of scientists who will advance our understanding in this crucial area of medical research. The MRC-PPU is located in a beautiful setting overlooking the estuary of the River Tay and embedded within the School of Life Sciences at the University of Dundee.

We are one of the UK’s leading universities – internationally recognised for our expertise across a range of disciplines and research breakthroughs in multiple areas, including science, medicine and engineering, amongst many others. Conveniently located on the banks of River Tay, our main city-centre campus is at the heart of Dundee - an up-and-coming, friendly, compact and affordable city with a rich heritage in design and technology. Just a short walk from the V&A Museum of Design Dundee, we’re close to both the train and bus stations. We also have campuses at Ninewells Hospital and in Kirkcaldy which are easily accessible via local transport links.

The diversity of our staff and students helps to make the University of Dundee a UK university of choice for undergraduate, postgraduate and distance learning. Family friendly policies, staff networks for BME, Disabled and LGBT staff, membership of Athena SWAN, the ECU Race Equality Charter and Stonewall as well a full range of disability services, create an enjoyable and inclusive place to work.