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MRC DTP 4 Year PhD Programme: Targeting E3 ubiquitin ligases with small molecules


About This PhD Project

Project Description

This project is offered as part of the University of Dundee 4-year MRC DTP Programme “Quantitative and Interdisciplinary approaches to biomedical science”. This PhD programme brings together leading experts from the School of Life Sciences (SLS), the School of Medicine (SoM) and the School of Science and Engineering (SSE) to train the next generation of scientists at the forefront of international science. The outstanding biomedical research at the University of Dundee was recognised by its very high rankings in REF 2014, with Dundee rated as the top University for Biological Sciences in the UK. A wide range of projects are available within this programme crossing exceptional strengths in four key areas: Infection and Disease; Responses to Cellular Stresses; Development, Stem Cells and Neurobiology; and Big Data and Translation. All students on this programme will receive training in computational biology, mathematical biology and statistics to equip with the quantitative skills in tackling complex biological questions. In the 1st year, students will carry out 3 rotation projects prior to selection of the final PhD project.

E3 ubiquitin ligases are enzymes within the ubiquitin-proteasome system (UPS) that catalyse the transfer of ubiquitin to specific substrate proteins. Targeting of E3 ligases with small molecules is a frontier goal of chemical biology and drug discovery because it allows: 1) enhanced selective intervention in the UPS, compared for example to proteasome inhibitors; 2) co-optingthe UPS to induce the degradation of new target proteins. For example, E3 ligase ligands can be incorporated into bifunctional chimeric molecules, nick-named proteolysis targeting chimeras (PROTACs), that induce protein ubiquitination and subsequent degradation inside the cell. However, only few E3 ligases have been successfully targeted with small molecules, and this requires the targeting of proteins surfaces or protein-protein interactions that are difficult-to-target (1).

The Ciulli lab works on developing E3 ligase targeting ligands and PROTACs. They have pioneered the structure-guided design and optimization of molecules targeting the von Hippel-Lindau (VHL) E3 ligase. They qualified potent and selective VHL inhibitor VH298 as a chemical probe of the VHL-HIF axis in the hypoxia signaling pathway. Moreover, they have shown how the VHL ligands can be successfully conjugated to a variety of protein-targeting ligands, yielding PROTACs active against diverse target proteins in cells and in vivo (2).

The Virdee lab has pioneered the development of novel chemical reagents andtools for studying the UPS, with a particular focus on E3 ligases. A key achievement is the development of probes that measure the hallmark trans-thiolation activity of ubiquitination enzymes. These have been used to gain insights into disease relevant E3regulation and have potential as biomarkers for diseases of unmet clinical need. Application of these technologies has led to the identification of a new class of E3 ligase with non-lysine ubiquitination activity (3). This project aims to develop novel small molecule binders for new E3 ligases of biological and therapeutic relevance. The project is designed as highly interdisciplinary, drawing on complementary expertise from both the Ciulli lab and Virdee labs. The student will receive outstanding training in multidisciplinary areas in cutting-edge research in fundamental and translational chemical and structural biology from both the Ciulli and Virdee labs.

References

References

1.BulatovE, Ciulli A. Biochem J 2015; 467:365–86.

2.Maniaci C, Ciulli A. Curr Opin Chem Biol2019; 52:145–56.

3.Pao K-C et al. Nature2018; 556:381–5.

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