Table 2.

Summary of protein degradation technologies

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, 127–129]
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, 130–132]
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]