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Targeting ubiquitin ligases with small molecules to develop new therapeutics (CHANTRYAU20SCIO)

Project Description

Ubiquitination (the addition of ubiquitin to specific proteins) is a key regulatory mechanism for cellular processes such as protein turnover via the ubiquitin-proteasome system (UPS), trafficking, autophagy, subcellular localisation, transcription and DNA repair. Ubiquitin transfer happens in three steps: activation, conjugation, and ligation, with substrate specificity provided by the last step, performed by E3 ubiquitin (Ub) ligases. Not surprisingly, dysregulation of the ubiquitin system, and E3 Ub ligases in particular, is associated with a wide range of diseases including cancer, cardiac fibrosis, neurodegeneration, immune disorders and infectious diseases. Consequently, targeting of E3 ligases with small molecules is a frontier cutting-edge goal of chemical biology and drug discovery. In this proposal, we focus our efforts on developing small molecule inhibitors and binding fragments that selectively target E3 Ub ligases, and in particular two known as WWP1 and WWP2 that have been shown to increase the risk and promote the growth/spread of human cancers. The experimental approach will combine 3D structure informed organic synthesis and modification of known inhibitors with traditional high-throughput assay screening of compound libraries, and linked to biophysical and fragment-based crystallographic refinement of lead compounds. The project will provide an excellent opportunity for a PhD student to gain experience in a range of multidisciplinary techniques (structural biology, chemical synthesis, mechanistic enzymology, whole cell studies) to probe the functionality of different ligands at both the cellular and molecular level, as well as training in a wide-range of multi-faceted skills relevant to the study of normal and disease-specific biology.

For more information on the supervisor for this project, please go here https://people.uea.ac.uk/a_chantry
This is a PhD programme.
The start date of this project is 1 October 2020.
The mode of study is full-time.
The studentship length is 3 years. Please note 3 year studentships have a (non-funded) 1 year ‘registration only’ period.

Entry requirements: acceptable first degrees are Biological Sciences, Biochemistry, Medicinal Chemistry, and related Bioscience degree

The standard minimum entry requirement is 2:1.

Funding Notes

This PhD project is in a competition for a Faculty of Science funded studentship. Funding is available to UK/EU applicants and comprises home/EU tuition fees and an annual stipend of £15,009 for 3 years. Overseas applicants may apply but they are required to fund the difference between home/EU and overseas tuition fees (which for 2019-20 are detailed on the University’s fees pages at View Website . Please note tuition fees are subject to an annual increase).

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