Emerging TPD technologies
| TPD Technology . | Description . | Utility . | Considerations . | References . |
|---|---|---|---|---|
| AbTACs | Use bispecifc antibodies to engage target membrane proteins and trigger internalization and degradation | Enable targeting of membrane proteins (eg, PD1; beyond capability of orthodox PROTACs) | Require cell surface E3 ligases such as ZNRF3 and RNF43 | 132 |
| Oligonucleotide-based PROTACs | Use oligonucleotide motifs as PROTAC warhead Various oligonucleotide formats: single- or double-stranded DNA, RNA, or G-quadruplexes | Enable targeting of TFs and RNA-binding proteins via their nucleic acid–binding domains | Compared to orthodox PROTACs, greater challenges with cell permeability and target cell access | 133,134 |
| Multitargeted PROTACs | Target multiple proteins simultaneously via 1 molecular construct | Tractable multiplexed targeting | Increases complexity of E3 ligase selection Likely increased risk of nontarget neosubtrate degradation, risk of off-target toxicity | 135 |
| BioPROTACs | Engineered fusion proteins, E3 ligase substrate recognition domain modified to express target-specific peptide or protein | Dispenses with warhead identification and ternary complex optimization; can be delivered as mRNA | Unable to be administered orally; delivery is challenging | 136-140 |
| Pre-PROTACs | PROTACs that are only activated by specific stimuli or contexts. Examples: light activated, radiograph activated, and hypoxia or ROS triggers | Improve spatiotemporal and cellular contextual control of PROTAC activity; thus, reduce dose requirements, reduced toxicity | Alternative physical, chemical, or electromagnetic stimuli could be used if suitable sensor moieties are identified | 141-147 |
| MGs | Induce colocalization of target protein and E3 ligase. Example: lenalidomide and pomalidomide. | Smaller molecular size than conventional PROTACs but superior PK | Limited design flexibility | 148-150 |
| Lysosome-mediated TPD LYTACs AUTACs ATTECs AUTOTACs MoDE-As | Leverage lysosomal non-UPS protein cycling cellular processes: (1) autophagy-lysosomal system degrades cytoplasmic proteins, protein aggregates, and organelles; (2) endosome–lysosomal pathway that degrades extracellular proteins | Expands the range of protein, protein structures, and other biomolecules targetable with TPD therapeutics beyond those subject to the UPS | Early in development | 151-153 |
| TPD Technology . | Description . | Utility . | Considerations . | References . |
|---|---|---|---|---|
| AbTACs | Use bispecifc antibodies to engage target membrane proteins and trigger internalization and degradation | Enable targeting of membrane proteins (eg, PD1; beyond capability of orthodox PROTACs) | Require cell surface E3 ligases such as ZNRF3 and RNF43 | 132 |
| Oligonucleotide-based PROTACs | Use oligonucleotide motifs as PROTAC warhead Various oligonucleotide formats: single- or double-stranded DNA, RNA, or G-quadruplexes | Enable targeting of TFs and RNA-binding proteins via their nucleic acid–binding domains | Compared to orthodox PROTACs, greater challenges with cell permeability and target cell access | 133,134 |
| Multitargeted PROTACs | Target multiple proteins simultaneously via 1 molecular construct | Tractable multiplexed targeting | Increases complexity of E3 ligase selection Likely increased risk of nontarget neosubtrate degradation, risk of off-target toxicity | 135 |
| BioPROTACs | Engineered fusion proteins, E3 ligase substrate recognition domain modified to express target-specific peptide or protein | Dispenses with warhead identification and ternary complex optimization; can be delivered as mRNA | Unable to be administered orally; delivery is challenging | 136-140 |
| Pre-PROTACs | PROTACs that are only activated by specific stimuli or contexts. Examples: light activated, radiograph activated, and hypoxia or ROS triggers | Improve spatiotemporal and cellular contextual control of PROTAC activity; thus, reduce dose requirements, reduced toxicity | Alternative physical, chemical, or electromagnetic stimuli could be used if suitable sensor moieties are identified | 141-147 |
| MGs | Induce colocalization of target protein and E3 ligase. Example: lenalidomide and pomalidomide. | Smaller molecular size than conventional PROTACs but superior PK | Limited design flexibility | 148-150 |
| Lysosome-mediated TPD LYTACs AUTACs ATTECs AUTOTACs MoDE-As | Leverage lysosomal non-UPS protein cycling cellular processes: (1) autophagy-lysosomal system degrades cytoplasmic proteins, protein aggregates, and organelles; (2) endosome–lysosomal pathway that degrades extracellular proteins | Expands the range of protein, protein structures, and other biomolecules targetable with TPD therapeutics beyond those subject to the UPS | Early in development | 151-153 |
ATTECs, autophagosome tethering compounds; AUTACs, autophagy-targeting chimeras; AUTOTACs, autophagy-targeting chimeras; LYTACs, lysosome-targeting chimeras; MoDE-As, molecular degraders of extracellular proteins through the asialoglycoprotein receptor; mRNA, messenger RNA; PD1, programmed cell death protein 1; ROS, reactive oxygen species; TPD, targeted protein degradation.