Table 1.
The inhibitors of E3 ligases.
| Drug Class | Agent | Mechanism | Tumor Types | Phase | Reference |
|---|---|---|---|---|---|
| RING-type E3 ligase inhibitor | |||||
| IAPs antagonists | LCL161 | Smac mimetic, induces degradation of cIAP-1 | Advanced solid tumors, hematologic neoplasms | 1, 2 | [3,156,157] |
| APG-1387 | Smac mimetic, induces proteasomal degradation of IAPs | Advanced solid tumors, hematologic neoplasms | 1, 2 | [158] | |
| Debio 1143 (AT-406) | Smac mimetic, inhibiting XIAP, cIAP-1 and cIAP-2 to promote apoptosis | Advanced solid tumors, lymphomas | 1, 2 | [159] | |
| Birinapant (TL32711) | Smac mimetic | Advanced solid tumors, hematologic neoplasms | 1, 2 | [160] | |
|
AEG40826/ HGS1029 |
Smac mimetic | Advanced solid tumors | 1 | [159,160] | |
| Compound 1 (GDC-0152) | Smac mimetic, binds to the BIR3 domains of cIAP1, cIAP2, and XIAP | Solid tumors | 1 | [161] | |
| Compound 13 (AEG40730) | Smac mimetic, binds to the BIR3 domains of cIAP1, cIAP2, and XIAP | N/A | Preclinical | [159] | |
| MDM2 antagonists | AMG 232 | Binds to MDM2 and inhibits the MDM2–p53 interaction | Advanced solid tumors, hematologic neoplasms | 1 | [3,162,163,164,165] |
| APG-115 | Targeting MDM2-p53 pathway | Advanced solid tumors, hematologic neoplasms | 1, 2 | [164,166] | |
| RG7112 | Binding to the p53 pocket on MDM2, effectively inhibits the MDM2-p53 interaction |
Advanced solid tumors, hematologic neoplasms | 1 | [3,164] | |
| SAR405838 (MI-77301) |
Binds selectively to HDM2, an oral spirooxindole derivative antagonist of HDM2 | Neoplasm malignant | 1 | [167] | |
| Idasanutlin (RG7388) | Blocking the MDM2–p53 interaction to reactivate the p53 pathway | Advanced solid tumors, hematologic neoplasms | 1, 2 | [168] | |
| Nutlin-3a | Inhibits the MDM2-p53 interaction, leading to p53 stabilization and activation of the p53 pathway | N/A | Preclinical | [169,170] | |
| HLI98 | Inhibits HDM2’s E3 activity | N/A | Preclinical | [171] | |
| MEL23, MEL24 | Inhibits the E3 ligase activity of the Mdm2-MdmX complex. | N/A | Preclinical | [172] | |
| pVHL antagonists | Compound 15, Compound 7, VH298 | The targeting of VHL disrupts the interaction of VHL with HIF-α | N/A | Preclinical | [173,174] |
| SKP2 antagonists | Compound A | Blocks the assembly of Skp2 into the SCF complex. | N/A | Preclinical | [175] |
| C1, C2, C16, C20 |
Inhibits Skp2-Cks1-p27 interface and thereby inhibit p27 ubiquitination. | N/A | Preclinical | [176] | |
| Compound 25 | Prevents the formation of the Skp2-Skp1 complex and inhibits the activity of SCF-Skp2. | N/A | Preclinical | [177] | |
| DT204 | Reduces the binding of Skp2 to Cullin-1 and Commd1, a Cullin-1-binding protein, therefore decreasing SCFSkp2 ubiquitin ligase activity | N/A | Preclinical | [178] | |
| Betulinic acid (BA) | Binding to Skp2 decreases its stability by disrupting Skp1-Skp2 interactions, thereby inhibiting the Skp2-SCF E3 ligase and promoting the accumulation of its substrates | N/A | Preclinical | [179] | |
| Dioscin | A new Skp2 inhibitor | N/A | Preclinical | [180,181] | |
| Curcumin, Quercetin, Lycopene, Silibinin, Epigallocatechin-3-gallate, Vitamin D3 | Natural agents that inhibit the expression of Skp2 in human cancers | Variety tumors | 1,2,3,4 | [7] | |
| β-TrCP antagonists | Erioflorin | Inhibits the interaction of Pdcd4/β-TrCP1 | N/A | Preclinical | [182] |
| GS143 | Inhibits β-TrCP1 ubiquitination of IkB, suppresses NF-kB signaling | N/A | Preclinical | [3] | |
| UBP-036 | Competitive inhibition of substrate binding to β-TRCP | N/A | Preclinical | [183] | |
| Fbxo3 antagonist | BC-1215 | Disrupts the interaction of Fbxo3 with Fbxl2 | N/A | Preclinical | [184] |
| Met30 (yeast) antagonist | SMER3 | Inhibits SCF-Met30 effectively and selectively | N/A | Preclinical | [3] |
| Cdc20 antagonists | Tosyl-l-arginine methyl ester | Blocks the APC/C-Cdc20 interaction | N/A | Preclinical | [185,186] |
| Pro-TAME | Disrupted the APC-Cdc20/Cdh1 interaction to reduce APC activation | N/A | Preclinical | [187] | |
| Apcin | Binds to Cdc20 and inhibits APC/C-dependent ubiquitylation | N/A | Preclinical | [185,187] | |
| Withaferin A | Suppresses Cdc20 activity | N/A | Preclinical | [187] | |
| NAHA | Inhibits the expression of Cdc20 | N/A | Preclinical | [187,188] | |
| Ganodermanontriol (GDNT) | Inhibits cell proliferation via targeting Cdc20 | N/A | Preclinical | [187,189] | |
| TRAF6 antagonist | C25-140 | Reduces TRAF6 E3 ligase activity by interfering with the TRAF6–Ubc13 interaction | N/A | Preclinical | [190] |
| HECT-type E3 ligase inhibitor | |||||
| Itch antagonist | Clomipramine | Blocks p73 ubiquitylation by binding to ITCH and inhibiting its charging with Ub | N/A | Preclinical | [191] |
| NEDD4-1 antagonist | Indole-3-carbinol (I3C) analogues | The potent small molecule inhibitors of NEDD4-1 ubiquitin ligase activity | Adult solid tumor | 1 | [192,193] |
| WWP2 antagonist | Compound 20 | Binds to the WWP2 HECT domain | N/A | Preclinical | [194] |
| SMURF1 antagonists | Bortezomib | Downregulated the protein level of SMURF1 by inhibiting SMURF1 mRNA levels | Neoplasm Malignant | 1, 2, 3, 4 | [195] |
| HS-152 | Blocked SMURF1-mediated RHOB ubiquitination | N/A | Preclinical | [196] | |
| NEDD4 antagonist | Nitidine chloride | A promising inhibitor of NEDD4 | N/A | Preclinical | [197] |
| Non-specific HECT antagonist | Heclin | Induces conformational change in HECT domain to inhibit activity | N/A | Preclinical | [198] |
| HUWE1 antagonists | BI8622, BI8626 | Inhibits HUWE1 to stabilize assembly of Myc-repressive MIZ1 complex on Myc-activated target genes | N/A | Preclinical | [3] |
| E6AP antagonists | Compound 12 | Inhibits E6AP–p53 interaction | N/A | Preclinical | [3] |
| Lutolein, CAF024 | Binds to viral E6 protein and prevents its association with E6AP | N/A | Preclinical | [3] | |
| Lig1, Lig2, Lig3 | Inhibits E6-E6AP interaction | N/A | Preclinical | [199] | |
| N-acetyl phenylalanine | Prevents the trimerization of E6AP and inhibits its E3 functionality | N/A | Preclinical | [3] | |
| CM11-1 | Prevents the poly-ubiquitination of Prx1 and p53 by E6AP | N/A | Preclinical | [3] | |
| RBR-type E3 ligase inhibitor | |||||
| LUBAC antagonists | HOIPIN-8 | Inhibits LUBAC activity and suppresses linear ubiquitination-mediated NF-κb activation. | Human lung carcinoma A549 cells and HEK293T cells | Preclinical | [9] |
| BAY11-7082 | Inactivates the E2-conjugating enzymes Ubc13 and UbcH7 and the E3 ligase LUBAC | pre-B ALL, natural killer/T-cell lymphomas, gastric cancer | Preclinical | [18,200] | |
| Gliotoxin | Inhibits LUBAC and suppresses NF-κB activation | N/A | Preclinical | [201] | |
| Stapled peptides | Inhibits LUBAC through the disruption of the HOIL-1L-HOIP interaction and loss of the functional complex | N/A | Preclinical | [202] | |
| HOIP antagonist | Bendamustine | Specifically inhibits HOIP | Solid tumors, hematologic neoplasms | FDA approved (Phase 4) | [3] |
| N/A: not applicable | |||||