Until the 1980s, most scientists had little understanding of the cellular processes involved in the ubiquitin-proteasome system (UPS). Their primary focus at the time was how proteins were produced, not how they were broken down. Several scientists, however, wanted to understand the protein degradation process and how a specific “tag”, called ubiquitin, could signal to the proteasome to degrade and dispose of the marked proteins. In 2004, these scientists — Aaron Ciechanover, Avram Hershko and Irwin Rose – were awarded the Nobel Prize in Chemistry for the discovery of ubiquitin-mediated protein degradation.
This discovery provided important insights into other ubiquitin-mediated protein degradation processes like cell-division and DNA repair. It helped scientists understand the role of dysregulated protein degradation in certain diseases, and was the impetus for a new strategy to redirect this cellular process to treat diseases. Targeted protein degraders are bifunctional small molecules that can potentially hit these “undruggable” targets by harnessing the body’s natural cellular process for disposing of unwanted proteins.
“If companies want to access the other 80% of the proteome, their medicinal chemists will need to forge a new set of rules for how to rationally build drugs that consistently degrade proteins.”
New Way: Targeted Protein Degradation
Targeted protein degraders are bifunctional small molecules that can potentially target previously “undruggable” and difficult to drug proteins by harnessing the body’s natural cellular process to eliminate disease-causing proteins. They:
- Destroy and not just inhibit the targeted proteins
- Potentially target a large percentage of the previously undrugged proteome (over 80%) and, unlike small molecules, do not require an active site on proteins
- Can be designed for oral bioavailability
- Be highly targeted, selective and practical
- Remove the scaffolding function of targeted proteins essential in a number of disease-associated signaling pathways
The Rising Tide
The rapidly expanding science of targeted protein degradation, spurred by hundreds of millions of dollars in investments in just the last few years, has accelerated efforts to develop a new generation of therapies. With more than 80% of the proteome now at play, opportunities abound for companies that can define the rules for unlocking new biology through the power of this novel therapeutic modality.