Discovery and Investigation of small molecule protein-protein interaction stabilisers

• Funding – self-funded/externally sponsored applicants   (PhD Fees can be found here)
• Applications are accepted year round
• Standard Entry dates – January and September
• Applicants are expected to have a degree (equivalent of Honours or Masters) in a relevant discipline.

This project seeks to achieve breakthroughs in how Central Nervous System diseases, where there is severe unmet medical need, may be addressed with small molecules. Molecular glues are small molecules which can induce the proximity of cellular proteins to modify their function and subsequently impact cell health. This project will seek to develop new approaches for how molecular glues can be prospectively discovered, understand their mechanism of action and produce novel chemical probes to validate new therapeutic concepts. All projects within the Farnaby group are multi-disciplinary in nature and depending on the capabilities, background and ambitions of the candidate, the exact proportion of focus on the chemical (i.e. organic synthesis, medicinal chemistry) or biological (cellular assay development and mechanism of action studies) aspects of the project can be tailored. The project will seek to answer the following questions: 

• Can native protein-protein interactions be stabilised with small molecules to illicit cellular responses?
• Can new screening methods be identified to expedite molecular glue discovery?
• Can novel disease relevant molecular glue mechanisms of action be identified? 

The Farnaby group is based within the Centre for Targeted Protein Degradation and as such benefits from being in a world class, superbly equipped, multi-disciplinary environment. We are driven to identify innovative chemical tools with novel mechanisms for understanding and addressing diseases of central nervous system and other diseases. We use a combination of molecular & cellular biology, organic synthesis and chemoproteomics techniques. The group accesses the full range of expertise available across the School of Life Sciences including collaborators in other divisions such as the MRC-PPU and DDU where there is rich knowledge in CNS disease biology and in vivo Pharmacokinetics/Pharmacology. The candidate would benefit from opportunities to develop technical skills in any of the above disciplines throughout their studentship as well being supported and mentored in their professional development. 

This project will build on new discoveries made in the Farnaby Group focussed on novel molecular glue discovery and will benefit from close collaboration with related cellular pathway experts in the MRC-PPU as well as opportunities to interact with industry partners associated with Dr Farnaby's Group and the broader Centre for Targeted Protein Degradation. 

Dr Farnaby has made major contributions towards the understanding and translation of targeted protein degradation drug discovery. Previous to his groundbreaking discoveries in the application of PROTACs for cancer, he spent several years as a senior medicinal chemist in industry, co-inventing two central nervous system drugs currently in late-stage clinical trials.  

 References: 

Farnaby, Popow et al Targeting Cancer with small molecule pan-KRAS degraders 

BioRXIV doi:10.1101/2023.10.24.563163 

Kofink, C et al A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo 

Nat Commun 13, 5969 (2022).  

Farnaby et al, BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design 

Nat Chem Biol 15, 672-680 (2019) 

Our research community thrives on the diversity of students and staff which helps to make the University of Dundee a UK university of choice for postgraduate research.  We welcome applications from all talented individuals and are committed to widening access to those who have the ability and potential to benefit from higher education.