Structural and Mechanistic Chemical Biology of Degraders Mode of Actions
31 March 2024
Pioneering discoveries from the Ciulli Laboratory have contributed to the establishment of a new modality of chemical intervention into biological systems. The new paradigm-shift concept is that of targeting proteins for degradation using small molecules, instead of conventionally blocking or inhibiting target proteins. Protein degradation can be undertaken by bifunctional molecules, also known as protolysis-targeting chimeras (PROTACs), that recruit the target for ubiquitin mediated degradation by complexing them with E3 ubiquitin ligases, most-commonly the von Hippel-Lindau (VHL) and Cereblon (CRBN) E3 ligases. We are beginning to understand the rules of how to design and study this new class of molecules in order to trigger efficient, profound and selective downstream protein degradation, and the chemical properties necessary for 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 the newly announced Centre for Targeted Protein Degradation (CeTPD, https://www.dundee.ac.uk/cetpd) at Dundee. It takes a multidisciplinary approach including:
1. organic and medicinal chemistry and computational tools to design and achieve desired molecules;
2. structural biology and biophysics to study binary and ternary complexes in solution and reveal their structural and dynamic interactions; and
3. 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 Drug Discovery Unit. We collaborate with several research groups within the School, including the Divisions of BCDD, MRC-PPU, GRE, and CSI, 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 PROTACs 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
c. Fundamental structural and mechanistic studies of novel degrader modalities, e.g. homo-PROTACs and our recently described trivalent-PROTACs
The project can be tailored to the student specific interests and motivations. The potential impact of these investigations are directly in the area of translational chemical biology and drug discovery. Targeted Protein Degradation is one of the most exciting area with >4B$ invested in this area over the past 5 years.
Imaide, S. et al. Trivalent PROTACs enhance protein degradation via combined avidity and cooperativity Nat. Chem. Biol. 2021, 17 (11), 1157–1167
Bond, A.G., Craigon, C. et al. Development of BromoTag: A “Bump-and-Hole”–PROTAC System to Induce Potent, Rapid, and Selective Degradation of Tagged Target Proteins J. Med. Chem. 2021, 64 (20), 15477–15502
Ciulli, A., Trainor, N. A beginner’s guide to PROTACs and targeted protein degradation Biochem (Lond) 2021, 43 (5), 74–79
Ishida, T., Ciulli, A. E3 Ligase Ligands for PROTACs: How They Were Found and How to Discover New Ones SLAS Discov. 2021, 26 (4), 484-502
Testa, A. et al. Structure-Based Design of a Macrocyclic PROTAC Angew. Chem. Int. Ed. 2020, 59, 1727-1734
How to apply
This project is open to self-funded and externally sponsored applicants, standard entry dates are January and September but we will consider applications year round. If you are interested in applying, please contact the supervisor directly in the first instance to discuss further, principal supervisors will ask you about your qualifications and your research experience to determine your suitability for the project. You will also be asked to indicate how you intend to fund your PhD (PhD fee information can be found here).
For general enquiries, contact SLS-PhDAdmin@dundee.ac.uk