Targeted Protein Degradation
Beyond PROTACs: the expanding universe of induced proximity degradation. From ubiquitin-proteasome hijacking to lysosomal targeting and RNA cleavage, TPD modalities are redefining what it means to drug a target.
PROTACs
Heterobifunctional degraders that bridge a target protein and an E3 ligase (e.g. VHL, CRBN) to drive ubiquitination and proteasomal degradation.
Molecular Glue Degraders
Monovalent small molecules that stabilize neo-substrate interactions with E3 ligases, creating protein–protein interfaces that do not exist natively.
LYTACs
Lysosome-targeting chimeras that degrade extracellular and membrane proteins via the endo-lysosomal pathway.
Antibody-Based Degraders (AbTACs)
Bispecific antibodies that bridge a cell-surface target and a membrane-bound E3 ligase (e.g. RNF43, ZNRF3), routing the target through the endo-lysosomal pathway.
Autophagy-Targeting (AUTACs/ATTECs)
Chimeras that route large targets, organelles, and aggregates to the autophagy–lysosome system. ATTECs bind LC3 directly; AUTACs use a guanine-mimicking tag to trigger K63-ubiquitin–mediated selective autophagy.
RNA-Targeting (RIBOTACs)
Ribonuclease-targeting chimeras that recruit RNase L to a specific RNA target for site-directed cleavage. Selectivity comes from the small-molecule RNA binder, not from RNase L itself.
TPD Modality Comparison
| Modality | Mechanism | Target Location | E3 Ligase | Degradation Pathway |
|---|---|---|---|---|
| PROTACs | Bifunctional linker recruits E3 ligase to target | Intracellular | VHL, CRBN, IAPs | Ubiquitin-Proteasome (UPS) |
| Molecular Glues | Stabilizes neo-substrate interface on E3 ligase | Intracellular | CRBN, DCAF15 | Ubiquitin-Proteasome (UPS) |
| LYTACs | Conjugate binds lysosome-targeting receptor + target | Extracellular / Membrane | N/A | Endo-Lysosomal |
| AbTACs | Bispecific antibody bridges membrane E3 + target | Cell Surface | RNF43, ZNRF3 | Endo-lysosomal (ubiquitin-assisted) |
| AUTACs | S-guanine tag drives K63-polyUb → p62/LC3 capture | Intracellular / Organelles | K63-Ub (no single defined E3) | Autophagy-Lysosome |
| ATTECs | Bifunctional molecule tethers target directly to LC3 | Intracellular / Aggregates | N/A (ubiquitin-independent) | Autophagy-Lysosome |
| RIBOTACs | Recruits RNase L to target RNA | Intracellular (RNA) | N/A | RNase L Cleavage |
Interactive Tools
Why Kinetics Matter Across All TPD Modalities: Every TPD modality depends on induced proximity, and the duration and stability of that proximity complex shape degradation efficiency. For protein-targeting degraders (PROTACs, glues, LYTACs, AbTACs), SPR and BLI are the workhorses; RNA-targeting RIBOTACs and receptor-engagement assays for LYTACs/AbTACs typically rely on fluorescence anisotropy and cellular readouts in addition to label-free methods.