Targeted protein degradation (TPD) is emerging as a new way to treat diseases that works differently from traditional therapies and has several advantages. Instead of inhibiting a protein by binding to it and preventing it from functioning, TPD hijacks protein degradation pathways, such as the ubiquitin-proteasome system, that naturally exist in our cells to completely destroy dangerous proteins associated with diseases such as cancer. Complete removal of a protein from the cells disrupts all of it's potentional functions, potentially leading to a bigger impact than just inhibiting one function with a traditional drug. TPD also has the potential to expand druggable space, in that it can target "undruggable" proteins that are of high therapeutic interest but have proven resistant to targeting with conventional drugs. The TPD approach could also improve precision of therapies, targeting only diseased tissue and minimising side effects and damage to healthy tissue. There are two main types of molecules that are used in TPD: molecular glues and Proteolysis Targeting Chimeras (PROTACs). Both of these molecules work by sticking two proteins together, causing one protein, called the ligase, to tag the other protein (the target) with a molecule called ubiquitin. The ubiquitin tag is recognised by the cells garbage disposal system called the proteasome, which destroys the target protein.
Beyond disease therapy, TPD can also be used as a tool to help us understand normal and disease functions of proteins by removing them from healthy or diseased cells and looking at the consequences.
In order to advance TPD and enhance its prospects for creating treatments for diseases, we are exploring different components of the protein degradation pathway known as the ubiquitin-proteasome system to better understand how they work. We also hope to find small molecule drugs that can manipulate this pathway for therapeutic benefits.
