Hitting the Delete Button on Disease: The Rise of Targeted Protein Degraders
- Targeted Protein Degraders (TPDs) offer a revolutionary way to eliminate disease-causing proteins rather than just inhibiting them.
- This technology works by hijacking the cell’s natural protein disposal machinery, making it possible to target proteins previously considered “undruggable”.
- Structure-based computational methods are rapidly expanding the number of known targets for TPDs, opening up new avenues for treating cancer and other diseases.
- Recent Trends in Structural Biology: Insights from the PSDI Conference:
https://3decision.discngine.com/blog/2025/1/10/recent-trends-in-structural-biology-insights-from-the-psdi-conference - Discovery on Target Conference: The Industry’s Preeminent Event on Novel Drug Targets:
https://www.discoveryontarget.com - Drug Discovery Blogs and Influencers: Sparking Research Ideas:
https://drughunter.com/resource/drug-discovery-blogs
For decades, the dominant strategy in drug discovery has been inhibition. Scientists designed small molecules to fit into the active site of a disease-causing protein, like a key in a lock, to block its function. While this approach has produced many life-saving medicines, it has a fundamental limitation: it only works on proteins with well-defined binding pockets. A vast landscape of proteins, estimated to be over 85% of the proteome, lacks these “druggable” sites, leaving them beyond the reach of conventional therapies. These “undruggable” targets have long represented a frustrating frontier in medicine, implicated in cancers and other serious diseases with no viable treatment options.
A new therapeutic modality, Targeted Protein Degradation (TPD), is breaking down this barrier. Instead of merely inhibiting a target, TPDs hijack the cell’s own natural disposal system—the ubiquitin-proteasome system—to completely eliminate the disease-causing protein. These bifunctional molecules act like a microscopic matchmaker, with one end binding to the target protein and the other end recruiting a ubiquitin ligase. This forced introduction flags the target for destruction, effectively hitting the delete button on the protein. This approach is revolutionary because it doesn’t require a functional active site; it only needs a small nook or cranny on the target protein to bind to.
This technology is unlocking the “undruggable” proteome at an incredible pace. Researchers are now using structure-based computational approaches to mine the human proteome for new targets. One such strategy, starting from the structure of the Cereblon (CRBN) ubiquitin ligase, predicted over 1,400 new proteins that could be targeted for degradation, expanding the potential of this modality exponentially. By turning the entire protein into a potential target, TPDs are creating therapeutic possibilities for cancers and other diseases that were once considered intractable, heralding a new era of drug discovery where no protein is truly “undruggable.”