University of Dundee

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. 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. 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.