Table 3 Comparison of strategies that selectively target proteins for degradation
Method | Rate of action (t1/2) | Customized or universal ligand | Reversibility | Genetic manipulation required | Real-time visualization | Toxicity in mouse model | Degradation mediator |
|---|---|---|---|---|---|---|---|
Thalidomide-targeted degradation | < 1 h | Customized | Yes | No | No | No | CRL4aCRBN RING E3 ubiquitin ligase complex |
PROTACs | < 2 h | Customized | Yes | No | No | No | CRL4aCRBN and CRL2VHL E3 ligase |
HaloPROTACs | 4–8 h/1 h | Universal HaloPROTAC3/bestatin 1b | Yes | Yes, HaloTag7 / HaloTag fusion | Yes | N/A | CRL2VHL E3 ligase and IAP E3 ligase |
SMASh | N/A | Universal asunaprevir | Yes | Yes, self-cleaving NS3pro-NS4A fusion | N/A | No | NS3 protease from hepatitis C virus |
dTAG | < 1 h | Universal dTAG ligand | Yes | Yes, FKBP12 (F36 V) fusion | No | No | CRBN-dependent E3 ligase |
AID | < 1 h | Universal auxin (IAA) | Yes | Yes, AID tag fusion and Tir1 F-box protein expression | Yes | Yes | CRL1Tir1 |