Table 10.
Major small molecule PROTACs and their biological impacts
| Name | Target | Target ligand | E3 ligase | E3 ligase ligand | Biological impacts |
|---|---|---|---|---|---|
| SNIPER-1 | AR | DHT | cIAP1 | BE04 | Potential roles against AR positive disorders216 |
| SARM-nutlin PROTAC | AR | SARM | MDM2 | Nutlin | Potential roles against AR positive disorders214 |
| TKI-PROTAC-1 | BCR-ABL | TKI moiety (bosutinib and dasatinib) | CRL4 (CRB) | Pomalidomide | Reduced viability of chronic myelogenous leukemic cells238 |
| Compound MZ1 | BRD4 | JQ1 | CRL2 (VHL) | VHL binders | Suppression on oncogenic transcriptions associated with BRD4235 |
| ARV-771 | BRD4 | OTX015 | CRL2 (VHL) | HIF1α-derived and hydroxyproline-contained ligand | Tumor suppression in CRPC mouse models233; Induced apoptosis in MCL cells334 |
| Compound 23 | BRD4 | Azacarbazole | CRL4 (CRB) | Thalidomide | Growth suppression against xenograft leukemic tumors234 |
| dBET1 | BRD4 | JQ1 | CRL4 (CRB) | Phthalimide | Delayed leukemia progression in mice211 |
| CLIPTAC-1 | BRD4 | TCO-tagged JQ1 | CRL4 (CRB) | Thalidomide | Potential roles against BRD4 positive disorders237 |
| ARV-825 | BRD4 | OTX015 | CRL4 (CRB) | Pomalidomide | Suppressed proliferation and enhanced apoptosis in Burkitt’s lymphoma210; Induced apoptosis in MCL cells334 |
| TKI-PROTAC-2 | c-ABL | TKI moiety (dasatinib) | CRL2 (VHL) | HIF1α-derived and hydroxyproline-contained ligand | Potential roles against c-ABL positive disorders238 |
| TKI-PROTAC-3 | c-ABL | TKI moiety (bosutinib and dasatinib) | CRL4 (CRB) | Pomalidomide | Potential roles against c-ABL positive disorders238 |
| CDK9-PROTAC | CDK9 | Aminopyrazole analog | CRL4 (CRB) | Thalidomide | Potential roles against CDK9 positive disorders213 |
| Compound 4 | CRABP I/II | ATRA | cIAP1 | MeBS | Inhibited cell migration of neuroblastoma cells218,219 |
| brequinar-PROTAC | DHODH | Brequinar | CRL2 (VHL) | HIF1α-derived and hydroxyproline-contained ligand | Cytotoxicity against cancer cells239 |
| SNIPER-2 | ER | Estrone | cIAP1 | BE04 | Potential roles against ER positive disorders216,217 |
| CLIPTAC-2 | ERK1/2 | Probe 1 | CRL4 (CRB) | Thalidomide | Potential roles against ERK1/2 positive disorders237 |
| PROTAC_ ERRα | ERRα | Thiazolidinedione-based ligand | CRL2 (VHL) | HIF1α-derived and hydroxyproline-contained ligand | Potential roles against ERRα positive disorders203 |
| HT7-PROTAC-1 | FKBP12 | NS | ß-TRCP-HT7 | Chloroalkane | Potential roles against FKBP12 positive disorders230 |
| dFKBP | FKBP12 | Steel factor | CRL4 (CRB) | Phthalimide | against FKBP12 positive disorders211 |
| HT7-PROTAC-2 | FKBP12 | NS | Parkin-HT7 | Chloroalkane | Potential roles against FKBP12 positive disorders230 |
| SNIPER-3 | RAR | Ch55 | cIAP1 | BE04 | Potential roles against RAR positive disorders216 |
| PROTAC_ RIPK2 | RIPK2 | Vandetanib | CRL2 (VHL) | HIF1α-derived and hydroxyproline-contained ligand | Potential roles against RIPK2 positive disorders203 |
| SirReal-PROTAC | Sirtuin 2 | SirReal | CRL4 (CRB) | Thalidomide | Enhanced acetylation of the microtubule network212 |
| SNIPER (TACC3) | TACC3 | KHS101 | APC/C (CDH1) | Bestatin | Cytotoxic effects against cancer cells229 |
| PROTAC 3i | TBK1 | Aminopyrimidine chemotype | CRL2 (VHL) | HIF1α-derived and hydroxyproline-contained ligand | Potential roles against TBK1 positive disorders335 |
| Homo-PROTAC | VHL | VH032 | CRL2 (VHL) | VH298 | Self-degradation of E3 ligases231 |
Abbreviations: NS: not specific; ODD: oxygen-dependent degradation; E2-SMPI: Estradiol-Small molecule proteolysis inducer; SNIPER: specific and nongenetic IAPs-dependent protein erasers; AHR: aryl hydrocarbon receptor; AR: androgen receptor; ER: estrogen receptor; FKBP12: the 12-kDa FK506-binding protein; RAR: retinoic acid receptor; cIAP1: cellular inhibitor of apoptosis protein 1; SARM: non-steroidal androgen receptor ligand; MDM2: mouse double minute 2 homolog; BCR-ABL: TKI: tyrosine kinase inhibitor; BCR-ABL: breakpoint cluster region-abelson murine leukemia viral oncogene; BRD4: JQ1: a BET bromodomain inhibitor; BE04: a bestatin derivative that has affinity to cIAP1; CRPC: castration-resistant prostate cancer; CRABP: cellular retinoic acid-binding protein; ATRA: all-trans retinoic acid; MeBS: methyl bestatin; ERRα: estrogen-related receptor α; RIPK2: receptor interacting serine/threonine kinase 2; TACC3: transforming acidic coiled coil-containing protein 3; DHODH: dihydroorotate dehydrogenase; TBK1: TANK-binding kinase 1; MCL: mantle cell lymphoma; CDK9: cyclin-dependent kinase 9; SirReal: sirtuin rearranging ligand; SMC: small molecule compound; ERK: extracellular regulated protein kinase.