Pioneering discoveries from the Ciulli Laboratory and others have contributed to the establishment of a new modality of chemical intervention into biological systems. The new paradigm-shift concept is that of using small molecules to target proteins for degradation. This is fundamentally different from the conventional approach of blocking or inhibiting target proteins. Protein degradation can be achieved using bifunctional molecules, also known as proteolysis-targeting chimeras (PROTACs) or molecular glues, that recruit the target for ubiquitin-mediated degradation by bringing them into proximity to E3 ubiquitin ligases, most-commonly the von Hippel-Lindau (VHL) and Cereblon (CRBN) E3 ligases (see Figure). We are beginning to understand the rules of how to design, discover and study this new class of molecules in order to trigger efficient, profound and selective downstream protein degradation, and the rules and criteria that can guide drug discovery. These allow us to develop molecules that can support investigation of the consequences of targeted protein degradation and their therapeutic potential.
Our research in this area is conducted within our newly established Centre for Targeted Protein Degradation (CeTPD) at Dundee. It takes a multidisciplinary approach including:
- organic and medicinal chemistry and computational tools to design and develop desired molecules;
- structural biology and biophysics to study binary and ternary complexes in solution and reveal their structural and dynamic interactions; and
- chemical biology, biochemistry, proteomics and cell biology to study the cellular impact of our small molecules in relevant cellular systems – for example cancer cells sensitive to the knockdown of the protein target in question, or model cell lines suitable for biological investigation of specific signalling pathways.
Our science takes advantage of latest technologies and vast expertise available at the School of Life Sciences, not only within the new CeTPD but also within the FingerPrint Proteomics Facility and the cryo-EM Facility. We collaborate with several research groups within the School, including the Divisions of MRC-PPU, GRE, and DDU, to deploy our chemical tools to interrogate the biology of targets of interest and to dissect the functional consequences of disrupting the signalling networks in which they are involved.
Potential projects in this area range from:
a) Biological and functional studies in cells of potent and selective degraders for proteins of interest to us and/or collaborators, and evaluation of their potential as drug targets, particularly in cancer.
b) Identification, and biochemical, biophysical and structural studies of new E3 ubiquitin ligases for PROTACs and molecular glues
c) Fundamental structural and mechanistic studies of novel degrader modalities, e.g. our innovative chemistry approaches such as homo-PROTACs, trivalent-PROTACs and intra-molecular bivalent glues (IBGs)
The project can be tailored to the student’s specific interests and motivations.