Targeting the Ubiquitin–Proteasome System and Recent Advances in Cancer Therapy
Abstract
:1. Introduction
2. The Ubiquitination Reaction
2.1. Enzymes Involved in Ubiquitination Modification
2.2. Enzymes Involved in Ubiquitination Reversal
3. The Ubiquitination Code
4. Aberrant Ubiquitination in Cancer
5. Targeting Ubiquitination as a Therapeutic Approach to Cancer Treatment
5.1. Food and Drug Administration (FDA)-Approved Molecules in the Clinic
5.2. Major Achievements in Clinical Trials Targeting Ubiquitination
6. Developing Strategies to Target Ubiquitination in Cancer Therapy
6.1. Targeting Ubiquitin–Proteasome System to Modulate Tumor-Suppressor Proteins and Oncoproteins
6.2. Targeting Ubiquitin–Proteasome System to Induce Synthetic Lethality
7. Conclusions and Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Drug | Protein Target | Cancer Treatment |
---|---|---|
Bendamustine | E3 ligase linear ubiquitin assembly complex (LUBAC) | Multiple myeloma, chronic leukemia, rituximab/refractory follicular and low-grade lymphoma, ovarian cancer |
Thalidomide | E3 ligase cereblon (CRBN) | Myeloma |
Lenalidomide | E3 ligase cereblon (CRBN) | Myeloma |
Pomalidomide | E3 ligase cereblon (CRBN) | Myeloma |
Bortezomib (Velcade) | 26S Proteasome (β5) | Multiple myeloma, mantle cell lymphoma |
Carfilzomib (Kyprolis) | 26S Proteasome (β5) | Multiple myeloma, mantle cell lymphoma |
Ixazomib (MLN2238, Ninlaro) | 20S Proteasome (β5) | Multiple myeloma |
Mitoxantrone | USP11, USP15 | Acute nonlymphocytic leukemia, prostate cancer |
6MP, 6TG | USP14, USP2a, PLpro | Acute lymphocytic leukemia |
E1, E2, and E3 Enzyme Inhibitors | ||||||
Drug | Target | ClinicalTrials.gov Identifier | Treatment | Phase | Cancer Type | Results * |
Tak-243 (MLN7243) | Ubiquitin-activating enzyme (UAE) | NCT02045095 | MLN7243 | Phase I | Advanced malignant solid tumors | 1 mg: CR = 0%, PR = 33%, SD = 67%, PD = 0% 2 mg: CR = 0%, PR = 0%, SD = 75%, PD = 25% 4 mg: CR = 0%, PR = 0%, SD = 100%, PD = 0% 8 mg: CR = 0%, PR = 0%, SD = 0%, PD = 100% 12 mg: CR = 0%, PR = 0%, SD = 50%, PD = 50% 18 mg: CR = 0%, PR = 0%, SD = 60%, PD = 40% |
MLN4924 (Pevonedistat) | NAE (E1) | NCT01862328 | MLN4924 Paclitaxel Gemcitabine Docetaxel Carboplatin | Phase I | Solid tumors | MLN4924 + Paclitaxel + Carboplatin: CR = 18% MLN4924 + Docetaxel: PR = 19% MLN4924 + Carboplatin: PR = 17% MLN4924 + Paclitaxel + Carboplatin: PR = 36%–40% |
NCT02122770 | MLN4924 Fluconazole Itraconazole Docetaxel Carboplatin Paclitaxel | Phase I | Advanced solid tumors | MLN4924 + Docetaxel: OR = 10.5% MLN4924 + Carboplatin or Paclitaxel: OR = 22.2% | ||
NCT03057366 | Pevonedistat [14C]-Pevonedistat Docetaxel Carboplatin Paclitaxel | Phase I | Advanced solid tumors | Pevonedistat + Paclitaxel + Carboplatin: CR = 0%, PR = 0%, SD = 40%, PD = 60% Pevonedistat + Docetaxel: CR = 0%, PR = 0%, SD = 0%, PD = 100% | ||
NCT03330106 | Pevonedistat Docetaxel Carboplatin Paclitaxel | Phase I | Advanced solid tumors | Pevonedistat + Docetaxel: OR = 9.1% Pevonedistat + Carboplatin + Paclitaxel: OR = 8.3% | ||
NCT03486314 | Pevonedistat Rifampin Docetaxel Carboplatin Paclitaxel | Phase I | Advanced solid tumors | Pevonedistat + Docetaxel: CR = 0%, PR = 33.3%, SD = 33.3%, PD = 33.3% Pevonedistat + Carboplatin + Paclitaxel: CR = 0%, PR = 14.3%, SD = 42.9%, PD = 42.9% | ||
NCT01814826 | MLN4924 Azacitidine | Phase I | Acute myelogenous leukemia | MLN4924 (20 mg/m2) + Azacitidine (IV administration): CR = 43%, PR = 14%, CRi = 4% MLN4924 (20 mg/m2) + Azacitidine (SB administration): CR = 33%, PR = 13%, CRi = 13% MLN4924 (30 mg/m2) + Azacitidine (IV administration): CR = 50%, PR = 0%, CRi = 0% | ||
NCT02610777 | Azacitidine Pevonedistat | Phase II | Myelodysplastic syndromes leukemia, myelomonocytic, chronic leukemia, myeloid, acute | Azacitidine: CR = 36%, OR = 45% Azacitidine + Pevonedistat: CR = 45%, OR = 51% | ||
LCL161 | RING-type E3 IAPs | NCT01617668 | LCL161 paclitaxel | Phase II | Triple negative breast cancer | LCL161 + paclitaxel (gene expression signature positive): CR = 24.9% Paclitaxel (gene expression signature positive): CR = 23.4% LCL161 + paclitaxel (gene expression signature negative): CR = 6.9% Paclitaxel (gene expression signature negative): CR = 9.1% |
NCT01955434 | LCL161 Cyclophosphamide | Phase II | Recurrent plasma cell myeloma refractory plasma cell myeloma | No results available on the CR, PR, SD, and OR | ||
TL-32711 (birinapant) | RING-type E3 IAPs | NCT01188499 | Birinapant, Carboplatin/Paclitaxel Irinotecan Docetaxel Gemcitabine Liposomal Doxorubicin | Phase I Phase II | Advanced or metastatic solid tumors | Carboplatin/paclitaxel + TL32711 Irinotecan + TL32711 Docetaxel + TL32711 Gemcitabine + TL32711 Liposomal doxorubicin percent patients overall across all five arms demonstrating CR or PR = 10% |
AT-406 (DEBIO1143) | IAPs | NCT04122625 | Debio1143 Nivolumab | Phase I Phase II | Solid tumor | Small cell lung cancer ORR = 0% Squamous cell carcinoma of the head and neck ORR = 0% Gastrointestinal cancers ORR = 0% Gynecologic cancers ORR = 9.1% |
Proteasome Inhibitors | ||||||
Drug | Target | ClinicalTrials.gov Identifier | Treatment | Phase | Cancer Type | Results * |
Marizomib | Proteasome (20S CS) | NCT00461045 | Marizomib | Phase II | Relapsed or relapsed/refractory multiple myeloma | CR = 0%, PR = 0%, SD = 26.7%, PD = 60%, NE = 13.3% |
NCT02330562 | Marizomib Bevacizumab | Phase I Phase II | Malignant Glioma Glioblastoma | Marizomib (0.55 mg/m2) +Bevacizumab: OR = 50% Marizomib (0.7 mg/m2) + Bevacizumab: OR = 33.3% Marizomib (0.8 mg/m2) + Bevacizumab: OR = 24.1% Marizomib (1 mg/m2) + Bevacizumab: OR = 20% | ||
DUB Inhibitors | ||||||
Drug | Target | ClinicalTrials.gov Identifier | Treatment | Phase | Cancer Type | Results * |
Disulfiram | USP21 USP2a | NCT02101008 | Disulfiram Chelated zinc | Phase II | Refractory disseminated malignant melanoma | No results available on the CR, PR, SD and OR |
NCT03034135 | Disulfiram/copper Temozolomide (TMZ) | Phase II | Recurrent glioblastoma | CR = 0%, PR = 0% |
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Spano, D.; Catara, G. Targeting the Ubiquitin–Proteasome System and Recent Advances in Cancer Therapy. Cells 2024, 13, 29. https://doi.org/10.3390/cells13010029
Spano D, Catara G. Targeting the Ubiquitin–Proteasome System and Recent Advances in Cancer Therapy. Cells. 2024; 13(1):29. https://doi.org/10.3390/cells13010029
Chicago/Turabian StyleSpano, Daniela, and Giuliana Catara. 2024. "Targeting the Ubiquitin–Proteasome System and Recent Advances in Cancer Therapy" Cells 13, no. 1: 29. https://doi.org/10.3390/cells13010029
APA StyleSpano, D., & Catara, G. (2024). Targeting the Ubiquitin–Proteasome System and Recent Advances in Cancer Therapy. Cells, 13(1), 29. https://doi.org/10.3390/cells13010029