Table 2.

Comparison of different degrader systems. AbTac: antibody-based PROTAC; ATTEC: autophagy tethering compound; AUTAC: Autophagy Targeting Chimera; AUTOTAC: AUTOphagy TArgeting Chimera; BIAC: bispecific aptamer chimera; CMA: chaperone-mediated autophagy; GlueTac; GlueBody Chimera; LYTAC: LYsosome TArgeting Chimera; Mode-A; molecular degraders of extracellular proteins through the ASGPR; PROTAC: PROteolysis TArgeting Chimera; RIBOTAC: RIBOnuclease TArgeting Chimera; RNA: ribonucleic acid; SNIPER: Specific and non-genetic inhibitors of apoptosis protein (IAP)-dependent protein eraser.

Degradation Pathways	Degradation Systems	Degradable Targets	Advantages	Limitations	Highest Phase
Ubiquitin-proteasome	PROTAC	Intracellular proteins	In vivo, oral, improved selectivity and efficiency, does not require tight binding, catalytic and substoichiometric, definite structure and mechanism	High molecular weight, high surface area	Phase II
	Molecular glue	Intracellular proteins	Good pharmacology, specific to ligase and substrate	Mainly relies on accidential discovery	Approved
	SNIPER	Intracellular proteins	Catalytic and substoichiometric, definite structure and mechanism	Dependent on E3 ligase IAPs	Exploratory
Autophagy	AUTAC	Cytoplasmic proteins, fragmented organelle	Broader targets	Lack of detailed mechanism for K63 ubiquitination	Exploratory
	ATTEC	Intracellular proteins, nonproteins	Broader targets, low molecular weight, good transmembrane activity, better pharmacokinetics	Lack of detailed interaction between LC3 and degraders, high molecular design costs, low versatility	Exploratory
	AUTOTAC	Degradation-resistant aggregates	Broader targets	Unclarified mechanism	Exploratory
	CMA-based	Transmembrane proteins, aggregates	High specificity	Low stability and delivery efficiency, dependent on cell penetrating peptides, limited therapeutic effects	Exploratory
Lysosomal	LYTAC	Extracellular proteins, membrane-associated proteins	Broader targets	Limited clinical applicability, required an antibody or a small synthetic peptide to maintain its characteristics, difficult to determine the optimal linking site, high molecular weight, induced immunogenicity	Exploratory
	MoDE-A	Extracellular proteins	Small in size, monodisperse and nonprotein based, well-tolerated immunogenicity	Relies on highly expressed ASGPR on hepatocytes	Exploratory
	BIAC	Membrane-associated proteins	Costless and easily synthesized	In the early stages	Exploratory
	AbTAC	Transmembrane proteins	Utilizes two specific binding sites of bispecific antibodies to recruit E3, simple optimization of binding properties, built of human parts, reduced immune response	High molecular weight	Exploratory
	GlueTAC	Cell surface proteins	Cell-type independent degradation strategy, high specificity and efficiency	In the early stages	Exploratory
Ribonuclease	RIBOTAC	RNA	Favorable pharmacokinetic profile, low concentration, catalytic	High molecular weight, slow cellular uptake	Exploratory