China Scholarship Council: Induced proximity chemistries for interrogating neurodegenerative diseases


   School of Life Sciences

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  Dr William Farnaby, Prof A Ciulli  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

The Farnaby group is pursuing an ambitious and exciting new programme to use induced proximity chemistry strategies for the development of Central Nervous System (CNS) targeted chemical probes. There are currently no disease modifying treatments approved for major diseases of the central nervous system, such as Alzheimer’s and Parkinson’s disease, which affect hundreds of millions of people globally. In other therapeutic areas such as Cancer, bifunctional molecules, also known as proteolysis-targeting chimeras (PROTACs) have been shown to be capable of inducing proximity of elements of the Ubiquitin Proteasome System (UPS) and directing them towards target proteins to induce degradation of these disease drivers. Whilst similar strategies would be of significant scientific and clinical value in CNS research, specific protein expression patterns and the requirement to access the brain via the blood brain barrier present extra challenges. Novel proximity inducing chemical strategies that can aid the validation and understanding of new therapeutic concepts in the central nervous system would have major impact on fundamental and translational research. 

This project will focus on developing novel synthetic chemistry and design methods to access libraries of proximity inducing molecules that will then be applied to high profile protein targets indicated in neurodegenerative disease. In doing so we will discover new biological mechanisms that can be co-opted for targeted protein degradation, stabilization or translocation in CNS cellular models and develop qualified chemical probes for high profile protein targets in the CNS research area.  

This project would allow the student to develop skills across synthetic and medicinal chemistry as well as being exposed to assay development and cell biology, providing the student training across disciplines.  

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. The vision for his group combines expertise in both induced proximity modalities and chemical biology and medicinal chemistry approaches in central nervous system research. The Farnaby group is based within the newly formed University of Dundee Centre for Targeted Protein Degradation and as such benefits from being in a world class, superbly equipped, multi-disciplinary environment. 

Furthermore, our 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 high throughput screening approaches respectively. We are also able to access other key capabilities such as the FingerPrint Proteomics Facility. 

The project can be tailored to the student specific interests and motivations. 

Biological Sciences (4) Chemistry (6)

Funding Notes

In order to be eligible for these awards applicants must:
Be a Chinese national
Meet the requirements of the CSC – please see their website
Hold an unconditional offer to study for a PhD at the University of Dundee and meet our English language requirements
Have completed a bachelors or masters degree before the agreed start of PhD study
Already have an IELTS score of 6.5 at time of applying
For further information on the CSC programme please visit https://www.dundee.ac.uk/phds/funding/china-scholarship-council-csc-programme and apply by completing our application form - https://dundee.onlinesurveys.ac.uk/csc-programme-2024-entry

References

References:
1. Christiane Kofink, Nicole Trainor, Barbara Mair,…, Harald Weinstabl*, William Farnaby*. A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo. Nat Commun 13, 5969 (2022). https://doi.org/10.1038/s41467-022-33430-6
2. William Farnaby*, Manfred Koegl*, Darryl McConnell, Alessio Ciulli. Transforming Targeted Cancer Therapy with PROTACs: A forward-looking perspective. Curr. Opin. Pharmacol. 57, 175-183 (2021), doi: 10.1016/j.coph.2021.02.009. Citations: 23
3. William Farnaby, Manfred Koegl, …, Darryl B. McConnell* & Alessio Ciulli*. Structure-based PROTAC design demonstrates BAF complex ATPase vulnerabilities in cancer. Nat. Chem. Biol. 15, 7, 672-680, doi: 10.1038/s41589-019-0294-6 (2019).

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