Targeted protein degradation represents a paradigm shift in drug discovery, offering a novel therapeutic approach that eliminates disease-causing proteins rather than simply inhibiting their function. Using the cell's natural degradation machinery—particularly the ubiquitin-proteasome system—degrader molecules can induce the destruction of specific proteins that have been considered "undruggable" by traditional approaches[1]. While still in early development for neurodegenerative diseases, this modality has achieved multiple approvals in oncology, validating the platform and generating significant interest for CNS applications.
PROTACs are bifunctional molecules with two distinct binding domains connected by a linker:
The resulting ternary complex brings the target protein into proximity with the E3 ligase, leading to[2]:
Key advantage: Substoichiometric activity — one PROTAC molecule can catalyze the destruction of multiple target molecules.
Molecular glues are smaller monovalent molecules that:
Examples: Thalidomide analogs (lenalidomide, pomalidomide) induce degradation of IKZF1, IKZF3, and other proteins.
| Drug | Company | Target | Indication | Status |
|---|---|---|---|---|
| Arvinas | ARV-110 | AR | Prostate cancer | Phase 2 |
| Arvinas | ARV-471 | ER | Breast cancer | Phase 2 |
| BMS | CC-90009 | GSPT1 | AML | Phase 1 |
| Nurix | NX-2127 | BTK | B-cell malignancies | Phase 1 |
While still preclinical, several programs are advancing:
| Program | Company | Target | Indication | Stage |
|---|---|---|---|---|
| Tau PROTAC | Arvinas | Tau | Alzheimer's disease | Preclinical |
| Tau molecular glue | Bristol Myers Squibb | Tau | Alzheimer's disease | Preclinical |
| TDP-43 degrader | Various | TDP-43 | ALS/FTD | Preclinical |
| Alpha-synuclein degrader | Various | Alpha-synuclein | Parkinson's disease | Discovery |
| LRRK2 degrader | Various | LRRK2 | Parkinson's disease | Discovery |
| Feature | PROTACs | ASOs | Antibodies | Small Molecules |
|---|---|---|---|---|
| Target | Protein | RNA/mRNA | Protein | Protein |
| Mechanism | Degradation | Reduced production | Clearance | Inhibition |
| CNS delivery | Poor | Good | Poor | Good |
| Dose frequency | Less frequent | Regular | Regular | Regular |
| Development stage | Preclinical | Approved/CNS trials | Approved | Approved |
| Cost | Unknown | High | Very high | Moderate |
Békés, M., Langley, D. R., & Crews, C. M. (2022). PROTAC targeted protein degraders: The past is prologue. Nature Reviews Drug Discovery. 2022. ↩︎
Paiva, S. L., & Crews, C. M. (2019). Targeted protein degradation: Elements of the next drug discovery era. Current Opinion in Chemical Biology. 2019. ↩︎