From: Beyond canonical PROTAC: biological targeted protein degradation (bioTPD)
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 | |
 | 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 | |
 | 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 | |
 | 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 | |
ClpCP proteases | BacPROTAC | Bacterial proteins | Small molecule/small molecule-peptide conjugate | Expand the targeted range to bacterial protein | Low efficiency | 2022 | [8] |