Table 2.
All compounds introduced in this perspective review.
| # | Administrated drug | Formulation | Receptor for endocytosis | Disease | Vector | Target Protein Ligand | E3 Ligand | Status | References |
|---|---|---|---|---|---|---|---|---|---|
| (1) | Anti-X-protein peptide-based PROTACs | PROTACs with the oligomerization domain, degron peptide, and R8 | Heparan sulfate proteoglycans | Cancer | R8 and X-entry as CPPs | Oligomerization domain of the X-protein as an X-protein ligand | Degron peptide of the X-protein as an E3 ligand | In vitro basic research | [17] |
| (2) | AP21998/ hypoxia inducible factor (HIF) 1α-based PROTAC | PROTAC with AP21998, ALAPYIP sequence, and D-R8 | Heparan sulfate proteoglycans | - | D-R8 as a CPP | AP21998 as an FK506 binding protein (FKBP12) ligand, | ALAPYIP sequence as a VHL ligand | In vitro Basic research | [18] |
| (3) | Dihydrotestosterone (DHT)/HIF 1α-based PROTAC | PROTAC with DHT, ALAPYIP sequence, and D-R8 | Heparan sulfate proteoglycans | Cancer | D-R as a CPP | DHT as an androgen receptor (AR) ligand | ALAPYIP sequence as a VHL ligand | In vitro Basic research | [18] |
| (4) | TH006 | Peptide-based PROTAC with a tau ligand, ALAPYIP sequence, and D-R8 | Heparan sulfate proteoglycans | Alzheimer’s disease | D-R as a CPP | Tau ligand | ALAPYIP sequence as a VHL ligand | In vitro Basic research | [19] |
| (5) | Peptide-based PROTAC | Peptide-based PROTAC with a tau ligand, Kelch-like ECH-associated protein-1 (Keap1) ligand, and D-R8 | Heparan sulfate proteoglycans | Alzheimer’s disease | D-R as a CPP | Tau ligand | Keap1 ligand as an E3 ligase ligand | In vitro Basic research | [20] |
| (6) | Peptide-based PROTAC | Peptide-based PROTACs with an α-synuclein ligand, the E3 ligase ligand, and TAT | Heparan sulfate proteoglycans | Parkinson’s disease | TAT as a CPP | α-Synuclein ligand | E3 ligase ligand | In vitro Basic research | [21] |
| (7) | Protac-1 as the first PROTAC | Protac with ovalicin and the IκBα phosphopeptide | - | - | -- | Ovalicin to bind methionine aminopeptidase-2 | IκBα phosphopeptide to bind β-TRCP contained in the Skp1-Cullin-F box E3 ligase complex | In vitro Basic research | [23] |
| (8) | The first small molecule-based PROTAC | PROTAC with a non-steroidal AR ligand and nutlin | - | Cancer | - | Non-steroidal AR ligand | Nutlin as an E3 ligase ligand | In vitro Basic research | [24] |
| (9) | ARV-110 as the first PROTAC entering the clinical trial test | PTOTAC with a non-steroidal AR ligand and a CRBN ligand | - | Cancer | - | Non-steroidal AR ligand | CRBN ligand | phase 1 phase 2 |
(Table 1) [25,26] |
| (10) | Eight PROTACs under clinical trials | Small molecule-based PROTAC with a target protein ligand and an E3 ligase ligand | - | Canceer | - | Target protein ligand | E3 ligase ligand | phase 1 | (Table 1) [25,26] |
| (11) | Three PROTACs under clinical trials including ARV-110 | Small molecule-based PROTAC with a target protein ligand and an E3 ligase ligand | - | Cancer | - | Target protein ligand | E3 ligase ligand | phase 1 phase 2 |
(Table 1) [25,26] |
| (12) | QC-01-175 | PROTAC with 18F-T807 derivative and a CRBN ligand | - | Alzheimer’s disease | - | 18F-T807 derivative as a tau ligand | CRBN ligand | In vitro Basic research | [30] |
| (13) | C004019 | PROTAC with ID220149 and a VHL ligand | - | Alzheimer’s disease | - | ID220149 as a tau ligand | VHL ligand | In vivo Basic research | [34] |
| (14) | I3 | PROTACs with THK5105 derivative and a CRBN ligand | - | Alzheimer’s disease | - | THK5105 derivative as a tau ligand | CRBN ligand | In vitro Basic research | [35] |
| (15) | Small molecule-based PROTACs | PROTACs with an α-synuclein ligand and a VHL ligand | - | Parkinson’s disease | - | α-Synuclein ligand | VHL ligand | In vitro Basic research | [36,37] |
| (16) | Small molecule-based PROTACs | PROTACs with a huntingtin ligand and a cIAP ligand | - | Huntington’s disease | - | Huntingtin ligand | cIAP ligand | In vitro Basic research | [40] |
| (17) | Idursulfase beta | Anti-transferrin receptor antibody fused to iduronate-2-sulfatase | Transferrin receptor | Hunter syndrome | Anti-transferrin receptor antibody | - | - | Launched in 2021 | [43] |
| (18) | Trastuzumab-PROTAC conjugate | PROTAC-antibody conjugate with a BRD4 ligand and a VHL ligand | HER2 | Cancer | Anti-HER2 antibody | BRD4 ligand | VHL ligand | In vitro Basic research | [46] |
| (19) | Anti-HER2 antibody-PROTAC conjugate | PROTAC-antibody conjugate with an ER ligand and a VHL ligand | HER2 | Cancer | Anti-HER2 antibody | ER ligand | VHL ligand | In vitro Basic research | [48] |
| (20) | STEAP1-5a | PROTAC-antibody conjugate with a BRD4 ligand and a VHL ligand | STEAP1 | Cancer | Anti-STEAP1 antibody | BRD4 ligand | VHL ligand | In vitro Basic research | [49] |
| (21) | STEAP1-9d | PROTAC-antibody conjugate with a BRD4 ligand and a VHL ligand | STEAP1 | Cancer | Anti-STEAP1 antibody | BRD4 ligand | VHL ligand | In vitro Basic research | [50] |
| (22) | NanoPROTACs covered with trastuzumab | PROTAC-encapsulated nanoparticles covered with antibodies | HER2 | Cancer | Anti-HER2 antibody | BRD4 ligand | VHL ligand | In vitro Basic research | [53] |
| (23) | PROTAC-antibody conjugate | PROTAC-antibody conjugate with a tau ligand and an E3 ligase ligand | Transferrin receptor | Alzheimer’s disease | Anti-transferrin receptor antibody | Tau ligand | E3 ligase ligand | Under analysis in Tashima lab | - |
| (24) | NanoPROTACs covered with antibodies | PROTAC-encapsulated nanoparticles covered with antibodies | Transferrin receptor | Alzheimer’s disease | Anti-transferrin receptor antibody | Tau ligand | E3 ligase ligand | Under analysis in Tashima lab | - |