Learn About Targeted Protein Degradation
Targeted protein degradation (TPD) is an emerging way to treat diseases that works by harnessing the body’s natural protein recycling system through a small molecule medicine to rapidly eliminate disease-causing proteins. The novel TPD field is quickly advancing investigational therapies that have the potential to overcome drug resistance mechanisms, reach disease-causing targets that are currently considered undruggable and ultimately improve patient outcomes.
The human body has a natural recycling system, known as the ubiquitin proteasome system (UPS), which identifies and breaks down proteins that are no longer needed for healthy function. The E3 ligase protein family manages this process by identifying proteins that are old, damaged, misfolded or otherwise ready for degradation.
When E3 ligases identify proteins to be degraded, they add a tag called ubiquitin. In quick succession, E3 ligases add numerous tags in a process known as polyubiquitination. Once polyubiquitination is complete, the target protein is sent to the proteasome, the cell’s natural recycling system. The proteasome degrades the target protein into amino acids, which can be recycled to form new proteins or excreted by the cell. Following target protein release, the E3 ligase is free to engage another target protein and repeat the ubiquitination process. In this way, the E3 ligase system can promote multiple rounds of target protein degradation. Each round is referred to as a catalytic cycle.
Small molecule medicines, called degraders, are able to redirect and promote this catalytic cycle against a disease-causing protein of choice. Degraders act as catalysts for this cycle by connecting an E3 ligase and a desired target protein together in a very specific position, called a ternary complex, so that the E3 ligase efficiently polyubiquitinates the target protein enabling its destruction by the proteasome. Each degrader molecule can catalyze many rounds of this cycle. In this way a single degrader molecule can eliminate many copies of its target protein.