About the Project
Can targeted protein degradation help eliminate cancer-causing viruses?
Human papillomavirus (HPV) is responsible for almost all cervical cancers and approximately 70–80% of HPV-positive throat cancers. Although highly effective vaccines prevent new infections, there are currently no medicines capable of eliminating established HPV infection. As a result, millions of people worldwide remain persistently infected and at risk of developing cancer.
HPV persists because infected cells evade immune surveillance during the latent phase of infection. Although the viral oncoproteins E6 and E7 continue to be expressed, HPV employs immune evasion strategies that result in low levels of MHC class I presentation of viral antigens. Consequently, infected cells escape recognition by cytotoxic CD8⁺ T cells, allowing persistent infection that can ultimately lead to cervical and oropharyngeal cancers.
Our recent unpublished work has demonstrated that targeted degradation of viral proteins using PROteolysis TArgeting Chimeras (PROTACs) enhances antigen presentation via the MHC class I pathway, leading to improved recognition of infected cells by antigen-specific CD8⁺ T cells. Building on these exciting discoveries, this project aims to develop the first PROTAC molecules targeting the HPV E7 oncoprotein, with the long-term goal of making persistent HPV infection visible to the immune system and enabling its elimination.
The research
The HPV18 E7 oncoprotein promotes cancer development through its interaction with the tumour suppressor protein PTPN14. The recently solved crystal structure of the E7–PTPN14 complex has enabled the discovery of the first small-molecule inhibitor capable of disrupting this interaction. Although this compound represents an exciting starting point, its modest potency means significant medicinal chemistry optimisation is required before it can be developed into a therapeutic.
This project offers the opportunity to discover and develop entirely new chemical matter against a challenging viral target, progressing from an initial hit molecule to first-in-class targeted protein degraders.
The project will involve:
- Resynthesis and validation of the reported E7 ligand as a chemical starting point.
- Application of advanced biophysical methods to confirm target engagement.
- Design and synthesis of focused analogue libraries to establish structure-activity relationships (SAR).
- Computational modelling and structure-based drug design to understand binding modes and guide compound optimisation.
- Rational design and synthesis of the first E7-targeting PROTAC molecules.
- Iterative optimisation of potency, molecular properties and degrader design using biological data generated through close collaboration with specialist immunology laboratories.
The biological evaluation of the compounds - including E7 degradation, restoration of PTPN14 levels, antigen presentation and T-cell recognition - will be undertaken in close collaboration with Professor Awen Gallimore's internationally recognised cancer immunology group. The student will work closely with Awen's team to interpret these biological data and use the findings to drive successive rounds of compound design and optimisation. There will also be opportunities to gain hands-on experience of biological techniques and to spend time within Professor Gallimore's laboratory, providing valuable insight into how medicinal chemistry integrates with translational cancer immunology.
This project provides a rare opportunity to contribute to the development of a first-in-class therapeutic strategy that combines modern medicinal chemistry with targeted protein degradation to tackle one of the most important unmet needs in cancer prevention.
Why join this project?
This PhD studentship brings together expertise from the Medicines Discovery Institute, the School of Chemistry and the Systems Immunity Research Institute, combining medicinal chemistry, computational chemistry, biophysics and cancer immunology within a single multidisciplinary drug discovery programme.
Working within this multidisciplinary environment, you will gain first-hand experience of how modern drug discovery programmes progress from an initial chemical starting point towards potential therapeutics.
Training and research opportunities
During this PhD you will develop expertise in modern medicinal chemistry and drug discovery, including:
Medicinal chemistry
- Multi-step organic synthesis
- PROTAC design and synthesis
- Structure-activity relationship (SAR) studies
- Compound purification and characterisation
Computational chemistry
- Molecular docking
- Structure-based drug design
- Binding mode prediction
- Computationally guided lead optimisation
Drug discovery
- Hit validation
- Biophysical characterisation of protein-ligand interactions
- Lead optimisation
- Rational design of targeted protein degraders
Collaborative translational research
- Working alongside leading cancer immunologists to evaluate compound activity
- Interpreting biological data to inform medicinal chemistry design
- Participating in multidisciplinary drug discovery project
Professional development
- Experimental design and data analysis
- Regular interaction with medicinal chemists, structural biologists and immunologists
- Scientific writing and communication
- Presentation at national and international conferences
- Publication in high-impact peer-reviewed journals
- Working within multidisciplinary academic collaborations
By the end of the PhD, you will have developed a highly sought-after skill set in medicinal chemistry, computational drug design and targeted protein degradation, together with experience of multidisciplinary drug discovery in a collaborative translational research environment. These skills will provide an excellent foundation for careers in the pharmaceutical and biotechnology industries or for further academic research.
How to apply:
You can apply online - consideration is automatic on applying for a PhD in Biosciences, with an October 2026 start date.
Please use our online application service at here and specify in the funding section state that you wish to be considered for Cancer Research Wales funding.
Please specify that you are applying for this particular project and the supervisor. Please provide a CV and supporting cover letter as part of your application.
Information on the application process can be found here.
Eligibility
As only one studentship is available and a very high standard of applications is typically received, the successful applicant is likely to have a very good first Chemistry degree (a First or Upper Second class BSc Honours or equivalent). Synthetic chemistry lab experience (desirable)
Application deadline
20 August 2026 - interviews (either in person or by Skype) being held at the end of August, early September.
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