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Table 2 Summary of protein degradation technologies

From: Protein degradation technology: a strategic paradigm shift in drug discovery

Degradation technology Target range Degradation pathway Advantages Potential problems Refs.
PROTAC Intracellular protein Proteasome pathway Targeted degradation of undruggable proteins
Specificity
Acceptable oral bioavailability (such as ARV-110 and ARV-471)
Clear degradation mechanism
High degradation efficacy
Large molecular weight
Poor oral bioavailability and other pharmacokinetic properties
Limited target range
Limited available E3 ligase
[21, 127,128,129]
SNIPER Intracellular proteins, cIAP1, and XIAP Proteasome pathway Simultaneous degradation of target protein and IAP, killing cancer cells that rely on IAP for survival
High specificity
Sufficient membrane permeability
Need an IAP ligand with high binding affinity
The degradation mechanism of cIAP1 and XIAP by the SNIPERs is not well understood
[79, 82, 88]
HaloPROTAC Endosomal proteins and HaloTag fusion protein Proteasome pathway Selectively induce target protein degradation; Improved drug-like properties The stoichiometric ratio of the chemical components to the protein needs to be labeled
The ability to knock the degradation label into the target protein needs to be improved
The Halo label itself may become the main target of ubiquitination and degradation
[89, 90, 130]
HyT Druggable or non-druggable proteins Proteasome pathway Some hydrophobic tags are independent of E3 ligases and ubiquitination
Wide range of potential targets
Universality
High affinity for the target protein ligand
The exact mechanism of action remains unclear
Potential perturbation of the unfolded protein response pathway may cause off-target effects
[96, 130,131,132]
LYTAC Extracellular and membrane-associated proteins Endosome/lysosome pathway Degradation does not depend on the UPS system
Degrade extra-membrane and membrane-related proteins
High controllability
Relative molecular mass is too large
There are few types of applicable shuttle receptors
Antibody may induce immune response
Non-catalytic, low degradation efficiency
[103, 104]
AUTAC Intracellular proteins and damaged organelles Selective autophagy pathway A wide range of potential targets, including damaged organelles such as mitochondria; Proteasome-independent Lack key information such as the specific molecular mechanism of K63 ubiquitination that mediates S-guanylation to trigger autophagy, as well as its efficiency and potential off-target effects
Possible influence on selective autophagy
[107, 109, 112]
ATTEC Cytoplasmic proteins and non-protein autophagy substrates Macro-autophagy pathway The relatively low molecular mass enables it to penetrate the blood–brain barrier
A wide range of potential targets
Mechanism of direct degradation
Lack of research on designing chimeras
Urgent need to clarify the chemical structure of the compound-protein interface
[113, 115]
RIBOTAC RNA Ribonuclease pathway It can degrade RNA at a low concentration Difficulties in finding small molecules that can selectively bind to the target RNA [125]