Table 3.

Advantages and limitations of the different TPD technology-based degradation systems.

Degradation pathways	Degradation system	Advantages	Limitations	Highest phase	Ref.
TPD via ubiquitin–proteasome	PROTAC	In vivo; do not require tight binding; improved selectivity and efficiency	High molecular weight (800 kDa) and high surface area; low solubility; poor cell permeability and low oral bioavailability; safety concerns	Phase II	[7], [59], [60]
	Molecular glue	Good pharmacology; specific to ligase and target	lack of rational design; poor in general substrate selectivity	Approved	[141]
	AID	Controllable protein degradation can be achieved through the addition time of Auxin.	Complicated experimental design; unclear activity of TIR1 in non-plant cells	Exploratory	[40]
	SMASh	FDA-approved HCV drug	Not suitable for studying biological process with fast kinetics; needs modification of SMASh system	Exploratory	[45]
	Trim-Away	Improved selectivity and efficiency	Poor cell membrane permeability; need introduction of antibody with complicated instruments	Exploratory	[90], [91]
TPD via endosome-lysosomal pathway	LYTAC	Independent of ubiquitination-proteasome degradation	Difficult to determine the optimal linking site; requires an antibody to maintain its characteristics; usually takes a few days	Exploratory	[118]
TPD via autophagy lysosome pathway	CMA-based degrader	Faster degradation rate, better reversibility; dose-dependence; stronger specificity; easy design strategy	Poor cellular membrane permeability	Exploratory	[128]
	AUTAC	Not only can degrade cytoplasmic proteins, but also achieve fragmented organelle degradation	Lack of detailed mechanisms	Exploratory	[127]
	ATTEC	Low molecular weight, good transmembrane activity, and better pharmacokinetics	High molecular design costs; low versatility	Exploratory	[133]
	AUTOTAC	Independent of ubiquitin on POI	Slow degradation rate	Exploratory	[136]