University of Dundee

4 Year MRC PhD iCASE Project: Drugging the undruggable with novel proteolytic AdPROM (Affinity-directed PROtein Missile) technology.

Protein malfunction, which can be caused by amplification or mutations, lies at the root of many human diseases. Therefore, individual proteins are often targeted for therapeutic interventions against many human diseases. However, it is thought that only a small percentage of proteins are ‘druggable’, meaning they can be targeted for therapeutic intervention by conventional drug approaches. The vast majority of the proteins still remain ‘undruggable’ and novel targeting strategies are required for us to be able to target these. Targeted proteolysis of endogenous proteins could offer a viable strategy to target the ‘undruggable’ proteome.

The Sapkota lab has developed an affinity directed protein missile (AdPROM) system that allows for rapid and efficient destruction of endogenous target proteins in many cell lines (1, 2). This approach permits rapid investigations into the functions of individual target proteins and the consequence of their destruction in specific disease states. The information then allows one to evaluate the viability of inducing proteolysis of a specific target protein as a therapeutic strategy. The Ciulli lab works on developing small molecule proteolysis targeting chimeras (PROTACs) that serve to target specific proteins in cells for their degradation via the ubiquitin proteasome system (3).

This project aims to apply the AdPROM technology to understand the function and evaluate the druggability of a number of ‘undruggable’ target proteins, which are involved in immune disorders, neurodegeneration and cancer. This list of target proteins will be chosen in collaboration with a major pharmaceutical company. After successful validation of druggability, one or two streamlined target proteins will be chosen for development of small molecule PROTACs. Additionally, the prospective student will develop novel methods to explore the feasibility of the AdPROM system itself as a potential therapeutic. The student will receive excellent training in cutting-edge technologies from the Sapkota and Ciulli labs and benefit immensely from the collaboration with pharmaceutical industry.

References:

1. Fulcher, L. J., Macartney, T. J., Turnbull, C., Hutchinson, L., and Sapkota, G. P. (2017) Targeting endogenous proteins for degradation through the affinity-directed protein missile system. Open biology 7: 170066

2. Fulcher, A. J., Macartney, T., Bozatzi, P., Hornberger, A., Rojas-Fernandez, A., and Sapkota, G. P. (2016) An Affinity-directed PROtein Missile (AdPROM) system for targeted proteolysis. Open biology 6:1602551.

Eligibility