Harnessing PROTAC Degraders to Develop Next-Generation Anti-thrombotic Therapies

About the Project

Blood clots are central to life-threatening conditions such as heart attacks and strokes. Current antithrombotic treatments, including COX inhibitors and P2Y12 antagonists, are effective at preventing recurrent clots but carry a significant risk of bleeding due to their broad effects on haemostasis. There is therefore a pressing need for new therapies that can prevent thrombosis without disrupting normal blood function. One challenge in discovering novel anti-thrombotic targets is the anuclear nature of platelets, which traditionally limits approaches to genetic animal models or small molecule inhibitors.

Our group has recently shown, for the first time, that Proteolysis Targeting Chimeras (PROTACs) can degrade intracellular proteins in human platelets, opening up exciting new possibilities in this rapidly advancing field. PROTACs are a powerful chemical biology tool that work differently from traditional inhibitors. Instead of temporarily blocking a protein’s activity, PROTACs recruit the cell’s own ubiquitin–proteasome system to tag and destroy specific proteins. This removes the protein entirely, including both its enzymatic and structural roles, producing long-lasting effects and enabling the study of proteins that are otherwise difficult to target.

Students on this project will gain hands-on experience in cutting-edge chemical biology techniques, including designing and testing PROTAC molecules. This is a unique opportunity to work at the interface of chemistry, molecular modeling, cell biology and translational research, tackling a major cardiovascular challenge. If you are interested in drug discovery, protein regulation, and translational science, this project offers a chance to contribute to exploration of the role of specific kinases in platelet function with the ultimate aim development of next-generation anti-thrombotic therapies.

Aims

The main aims of the project are as follows:

1. Design novel PROTACs targeting key platelet proteins involved in thrombosis.
2. Explore the effect of novel and existing PROTACs on their ability to degrade their target protein.
3. Evaluate the effect of targeted protein degradation on platelet activation and thrombus formation both in vitro and in vivo.
4. Establish PROTACs as a novel platform for discovering and validating anti-thrombotic targets.

Methods

Molecular modeling of PROTACs using warhead for chosen target and E3 ligase, cell culture, platelet isolation, western blotting and TR-FRET approaches to study protein expression and signalling, biophysical assays to determine ligand binding, functional platelet assays using flow cytometry, light transmission aggregometry, plate aggregometry, cell adhesion and spreading using confocal microscopy, clot retraction and in vitro and in vivo thrombus formation.

Supervisors

Dr Ingeborg Hers, Prof Varinder Aggarwal and Dr Robin Corey.

Keywords

Platelets, thrombosis, anti-platelet, chemical degraders, PROTAC, kinases, signalling, cell biology, chemistry, biochemistry.

University of Bristol, Bristol Medical School

Bristol Medical School is the largest and one of the most diverse Schools in the University of Bristol, with approximately 1100 members of staff, 1350 undergraduate, 250 postgraduate taught and 300 postgraduate doctoral research students. The Head of School is Professor Chrissie Thirlwell. The Medical School has two departments: Population Health Sciences and Translational Health Sciences. The School is a leading centre for research and teaching across these areas. Research in the School is collaborative and multi-disciplinary, with staff coming from a wide range of academic disciplines and clinical specialties.

How to apply for this project

This project will be based in Bristol Medical School – Translational Health Sciences in the Faculty of Health and Life Sciences at the University of Bristol. It could be adapted for any type of PGR degree. Use this information to search for the relevant programme in our online application system. Applicants should include the names of two supervisors (with their agreement after discussion of the research proposal). This project does not come with funding. If you have secured your own sponsorship or can self-fund this PGR degree please visit our information page for further information on the department of Translational Health Science and how to apply.