Table 1.

Summary of representative TPD technologies related to different degradation pathways

Pathway	TPD technologies	Target range	Composition	Advantages	Potential problems	Year	Refs
Proteasome	PROTAC	Intracellular	Small molecule/ biomacromolecule/ hybrid structure	Relatively high selectivity; Acceptable oral bioavailability; Clear degradation mechanism; Catalytic and sub-stoichiometric	Poor solubility for small-molecule PROTAC; Poor cell permeability; Poor PK properties; Limited target spectrum	2001	[11, 12]
	Molecular glue	Intracellular	Small molecule	Acceptable oral bioavailability.	Difficult to design	2010	[13]
	SNIPER	Intracellular	Small molecule	Simultaneous degradation of POIs and IAPs; High specificity	E3 ligase IAPs dependently	2010	[14]
	HyT	Intracellular/ extracellular	Small molecule/ Small-molecule peptide conjugate	Some hydrophobic tags are independent of E3 ligases and ubiquitination; Wide range of potential targets;	Incomplete POIs degradation; Unclear degradation mechanism; Potential off-target effects	2011	[15]
	Trim-away	Intracellular	Antibody	High specificity; Rapid degradation speed	Need extra Trim21; Unable to recycle	2017	[16]
Endosome- lysosome	LYTAC	Extracellular/ membrane proteins	Antibody	Degrade extracellular and membrane proteins; High controllability	Limited shuttle receptors; Potential immunogenicity; Non-catalytic; Low degradation efficiency	2020	[17, 18]
	AbTAC	Membrane proteins	Bispecific antibody	Degrade membrane proteins; High specificity	Large molecular weight	2021	[19]
	GlueTAC	Extracellular/ membrane proteins	Nanobody-peptide conjugate	High specificity; Sufficient membrane permeability by a cell penetration peptide	Short half-life in vivo	2021	[20]
	Bispecific Aptamer Chimeras	Membrane proteins	Aptamer	Easy to design and prepare; Good stability	Low delivery efficacy; Short half-life in vivo	2021	[21]
	Sweeping antibody	Extracellular	Antibody	Allow recycling;	Required engineering for each target	2013	[22]
	Seldegs	IgG	Antigen-Fc fusion proteins	Degrade autoantibodies; Lower dose	Required engineering for each target; Antigen selection	2017	[23]
Autophagy-lysosome	CMA-based degrader	Intracellular/ membrane proteins/aggregates	Chimeric polypeptides.	High specificity; High degradation efficacy	Low delivery efficacy; Low stability; Limited therapeutic effects;	2014	[24]
	AUTAC	Intracellular/ damaged organelles	Small molecule-poly(A) oligonucleotide conjugate	A wide range of potential targets; Proteasome-independent	Low degradation speed; Potential off-target effects; Dependent on K63 ubiquitination;	2019	[25]
	ATTAC	Intracellular/ non-protein	Small molecule	A wide range of potential targets; Blood-brain barrier permeability;	Difficult to design	2019	[26, 27]
	AUTOTAC	Intracellular/ protein aggregates	Small molecule	Degrade protein aggregates	Low degradation speed	2022	[28]
Ribonuclease	RIBOTAC	RNA	Small molecule/small molecule-poly(A) oligonucleotide conjugate	Expand targeted range to RNA; High degradation efficacy	Difficulties in finding specific ligands for targeting RNA	2018	[29, 30]
ClpCP proteases	BacPROTAC	Bacterial proteins	Small molecule/small molecule-peptide conjugate	Expand the targeted range to bacterial protein	Low efficiency	2022	[8]

Abbreviations: POI, Protein of interest; IAPs, Inhibitor of apoptosis protein; HyT, Hydrophobic Tag; PROTAC, Proteolysis Targeting Chimeras; TPD, Targeted protein degradation; PK, Pharmacokinetics; SNIPER, Specific and Non-genetic IAP-dependent Protein Erasers; Trim21, Tripartite motif-containing protein 21; LYTAC, Lysosome-targeting chimeras; AbTAC, Antibody-based PROTAC; IgG, immunoglobulin G; CMA, Chaperone mediated autophagy; AUTAC, Autophagy-targeting chimera; ATTAC, Autophagy-tethering compounds; AUTOTAC, AUTOphagy-TArgeting Chimera; RIBOTAC, Ribonuclease targeting chimera