Drug Development Targeting the Ubiquitin–Proteasome System (UPS) for the Treatment of Human Cancers
Abstract
:1. The Ubiquitin–Proteasome System Is Essential for the Maintenance of Protein Homeostasis
1.1. Tagging the to-Be-Degraded Proteins by Polyubiquitination
1.2. Proteolytic Degradation of the Polyubiquitinated Protein by the Proteasome Complex
2. The UPS Affects Tumorigenesis, Tumor Metabolism and Survival
2.1. The UPS and Tumorigenesis
2.2. The UPS and Tumor Metabolism
2.3. UPS and Tumor Survival
3. Inhibitors of the UPS in Cancer Therapies
3.1. Inhibitors of Ubiquitin-Activating Enzymes (E1s)
Compounds | Target | Modes of Action | Targeted Cancer Types in Preclinical Studies | Targeted Cancer Types in Clinical Studies or Therapies | Other Disease | Ref. |
---|---|---|---|---|---|---|
Inhibitors targeting 20S core particle of the proteasome | ||||||
Bortezomib | β5 > β1 | Inhibits the chymotrypsin-like activity of the proteasome by reversible binding to the β5 subunit thus inhibits proteasomal activity and leads to accumulation of polyubiquitinated proteins in cells | Multiple Myeloma Mantle cell lymphoma Acute myeloid leukemia lung cancers hepatocellular carcinoma Intrahepatic Cholangiocarcinoma Relapsed/Refractory Multiple Myeloma Neuroblastoma Colorectal Cancer Head and Neck Cancer Thyroid Carcinoma More cases to https://clinicaltrials.gov | Haemolytic anaemia Immune thrombocytopenia Lung disease Cold agglutinin disease Amyloidosis Macroglobulinemia | [98,99,100,101,102,103,104] | |
Carfilzomib | β5 | Covalent bonds to proteasome catalytic subunits, predominantly β5 | Multiple myeloma Relapsed and/or refractory multiple myeloma Lymphoma Chronic lymphocytic leukemia Thyroid cancer Refractory renal cell carcinoma Lung cancer More cases to https://clinicaltrials.gov | Pulmonary arterial hypertension | [105,106,107,108,109,110,111,112] | |
Ixazomib | β5 > β1 | First orally bioavailable proteasome inhibitor drug, predominantly targeting β5 | Multiple myeloma Refractory or relapsed multiple myeloma Acute myeloid leukemia Relapsed refractory acute myeloid leukemia Hodgkin and T-cell lymphoma Mantle cell lymphoma Non-hematologic malignancies lymphoma Breast cancer Glioblastoma Bladder cancer Renal cell carcinoma Waldenstrom macroglobulinemia Solitary osseous plasmacytoma More cases to https://clinicaltrials.gov | Al amyloidosis Autoimmune cytopenia HIV Lupus nephritis Kidney diseases | [113,114,115,116,117,118,119] | |
Oprozomib | β5 > β1 | A structural homologue of CFZ, orally available and applied to patients with relapsed after receiving BTZ- and CFZ-based therapies | Multiple Myeloma Relapsed and/or refractory multiple myeloma Hepatocellular carcinoma Waldenstrom macroglobulinemia Non-central nervous system malignancies | No reported applications | [120,121,122,123] | |
Marizomib | β5 > β2 > β1 | Irreversibly inhibits the activity of proteasome and more effectively induces apoptosis in tumor cells from MM and chronic lymphocytic leukemia patients, while shows a lower toxicity to normal cells than BTZ | Multiple Myeloma Relapsed and/or refractory multiple myeloma Ependymoma Non-small Cell Lung Cancer Pancreatic Cancer Melanoma Lymphoma Glioblastoma | No reported applications | [124,125,126,127,128] | |
Inhibitors targeting 19S regulatory particle of the proteasome | ||||||
IU1 IU1-47 | USP14 | Targets the thiol group in the active cysteine site in USP14 protease and significantly decrease cell proliferation, migration, and invasion. | Breast cancer Lung cancer | No reported applications | [129,130] | |
b-AP15 | USP14 UCHL5 | Targets both UCHL5 and USP14, disrupts the aggresome formation in cancer cells by activating caspase to further induce apoptosis relating to an upregulation of oxidative stress | Acute myeloid leukemia Multiple myeloma Large b cell lymphoma Mantle cell lymphoma Neuroblastoma Prostate cancer Breast cancer Lung cancer Head and neck cancer Colon cancer Ovarian cancer | No reported applications | [131,132,133,134,135,136,137,138,139,140,141] | |
VLX1570 | USP14 UCHL5 | An analog of b-AP15, more effective than b-AP15 in inhibiting tumor progression | See targeted cancer types of b-AP15 | Multiple Myeloma | No reported applications | [142,143,144,145] |
RA-9 | USP14 | Reacts with the sulfurs in the active site cysteine and inhibits proteasome-associated DUBs | Breast cancer Ovarian cancer Cervical cancer | Rheumatoid arthritis | [146,147] | |
WP1130 | UCHL5 USP14 USP9X | Directly inhibits USP9X in addition to UCHL5 and USP14, induces apoptosis and prevents drug resistance in malignancies through Mcl-1 degradation | Acute myeloid leukemia Chronic myelogenous leukemia Human mesothelioma Lung cancer Colon cancer Prostate cancer Hepatocellular carcinoma | No reported applications | [148,149,150,151,152,153,154] | |
OPA | RPN11 | A zinc ion chelator, inhibits the activity of RPN11 metal-containing enzymes of 19S and induces apoptosis including cell lines which are BTZ resistant | Multiple myeloma Hepatocellular carcinoma Cervical cancer Breast carcinoma | Sarcoidosis | [155,156,157,158,159,160,161] | |
8TQ | RPN11 | A strong RPN11-specific inhibition of proteasome 19S subunit and is a potent apoptosis inducer in MM cells | Lung carcinoma Colon cancer | No reported applications | [162] | |
Thiolutin | RPN11 | The reduced form of Thiolutin is an inhibitor of JAB1/MPN/Mov34 (JAMM) domain-containing metalloprotease RPN11 by chelating Zn2+-ions which is specifically toxic to cancer cells by hampering protein turnover | Only in cell free system | No reported applications | [163] |
Compounds | Target | Modes of Action | Targeted Cancer Types in Preclinical Studies | Targeted Cancer Types in Clinical Studies or Therapies | Other Disease | Ref. |
---|---|---|---|---|---|---|
ONX-0914 | β5i | The first epoxyketone-based peptidyl immunoproteasome selective inhibitor towards β5i | Rheumatoid arthritis (mouse model) | [164,165] | ||
PR-924 | β5i | An epoxyketone-based peptidyl selective inhibitor of β5i immunoproteasome, displays a much stronger inhibitory activity (β5c/β5i = 91) and blocks the growth of multiple myeloma in vitro and in vivo. | Multiple myeloma | [166,167] | ||
KZR-616 | β5i, β2i and β1i | The only epoxyketone-based peptidyl immunoproteasome selective inhibitor tested in clinic so far | Systemic lupus erythematosus (NCT03393013) | [168] |
3.2. Ubiquitin-Conjugating Enzymes (E2s) Inhibitors
3.3. Ubiquitin Ligases (E3s) Inhibitors
3.4. Inhibitors Targeting the Proteasome Complex
3.5. Inhibitors of 20S Proteasome Catalytic core Particle
3.5.1. Bortezomib: First-in-Class Proteasome Inhibitor
3.5.2. Carfilzomib: Second-in-Class Proteasome Inhibitor
3.5.3. Ixazomib: First Oral Proteasome Inhibitor Drug
3.5.4. Oprozomib: A Structural Homologue of CFZ
3.5.5. Marizomib
3.6. Inhibitors of 19S Proteasome Regulatory Particles
3.6.1. IU1
3.6.2. b-AP15
3.6.3. VLX1570
3.6.4. RA-9
3.6.5. WP1130
3.6.6. RA190
3.6.7. Ortho-Phenanthroline (OPA)
3.6.8. Quinoline-8-Thiol/Capzimin
3.6.9. Thiolutin
4. Targeting the Ubiquitin–Proteasome System (UPS) and Immune System in Cancer Therapies
4.1. Non-Selective Inhibitors of Immunoproteasome
4.2. Selective Inhibitors of Immunoproteasome
4.2.1. ONX-0914
4.2.2. PR-924
4.2.3. KZR-616
5. Concluding Remarks
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Compounds | Target | Modes of Action | Targeted Cancer Types in Preclinical Studies | Targeted Cancer Types in Clinical Studies or Therapies | Other Disease | Ref. |
---|---|---|---|---|---|---|
Inhibitors targeting E1s of the UPS | ||||||
PYR-41 | UBA1 | Irreversibly binds to the active cysteine in UBA1 and kill tumor cells by inhibiting cytokine-induced NF-κB activation, and promoting p53 accumulation | Prostate cancer Thyroid cancer | Hypertensive heart diseases/ Sepsis | [1,2,3,4,5,6] | |
MLN4924 | NAE | Covalently binds the nucleotide-binding site of NAE and generates a NEDD8-MLN4924 adduct that further undermines protein turnover leading to apoptosis in cancer cells | Liver cancer Pancreatic cancer | Acute Myelogenous Leukemia (AML) Multiple Myeloma Lymphoma Melanoma Lung Cancer Mesothelioma | Pulmonary inflammation/ Ipopolysaccharide-induced kidney damage/ Spinal cord ischemia-reperfusion injury/ Myelodysplastic Syndromes | [7,8,9,10,11,12,13,14,15,16] |
Inhibitors targeting E2s of the UPS | ||||||
CC0651 | hCdc34 | An allosteric inhibitor of human E2 enzyme hCdc34, causes large-scale structural rearrangements and affects the discharge of ubiquitin to acceptor lysine residues | Prostate cancer Colon cancer | No reported applications | [17] | |
NSC697923 | Ubc13–Uev1A E2 | Blocks the formation of the E2–Ub thioester conjugate and inhibits the activation of NF-κB signaling leading to reduced proliferation and cell viability | Melanoma B-cell lymphoma Neuroblastoma Colorectal Cancer | Diabetic nephropathy | [18,19,20,21,22] | |
Inhibitors targeting E3s of the UPS | ||||||
Nutlin-3a | Mdm2 | Competitively binds the Mdm2-P53 interacting site, activates P53 pathway, and thus results in cell cycle arrest, cell death, and growth inhibition | Acute/Chronic lymphocytic leukemia Hodgkin lymphoma Pancreatic cancer Glioblastoma Sarcoma Colon cancer Breast cancer Ovarian cancer Lung cancer Ewing sarcoma | Pulmonary arterial hypertension | [23,24,25,26,27,28,29,30,31,32,33,34,35] | |
RG7388 (R05503781) RG7112 (R05045337) | Mdm2 | The derivatives of nutlin-3a and Inhibits Mdm2-P53 binding site | Acute myeloid leukemia Relapsed or refractory Acute myeloid leukemia Multiple myeloma Relapsed multiple myeloma Glioblastoma Ovarian cancer Childhood sarcoma Neuroblastoma Breast cancer Lung cancer | Polycythemia vera/ Essential Thrombocythemia | [36,37,38,39,40,41,42,43] | |
GDC-0152 SM-406 | IAPs | Potent and orally bioavailable SMAC mimetic and antagonists of the inhibitor of IAPs with highly effective in induction of apoptosis in xenograft tumors, and is capable of inhibition of tumor growth | Osteosarcoma Leukemia Thyroid cancer Glioblastomas Breast cancer | No reported applications | [44,45,46,47,48] | |
SCF-12 | FBW7 | Blocks the substrate-binding pocket and impedes substrate recognition via inhibiting Cdc4 thus hinders tumor progression in colon and prostate cancers | Colon cancer Prostate cancer | No reported applications | [49] | |
Oridonin | FBW7 | Targets FBW7-c-Myc pathway and activates GSK-3, decreases c-Myc and induces apoptosis in leukemia and lymphoma cells | Myelogenous leukemia Breast cancer | Myocardial ischemia Reperfusion injury | [50,51,52] | |
Compound #25 | SKP2 | Directly binds SKP2, selectively suppresses Skp2 E3 ligase activity and exhibits potent antitumor activities in multiple animal models | Prostate cancer | No reported applications | [53] | |
NAHA | Cdc20 | Decreases Cdc20 expression and inhibits tumor proliferation in vitro and in vivo associated with the induction of apoptosis | Breast cancer | No reported applications | [54] | |
CM11-1 | E6AP | Acts as an E6AP inhibitor that prevents polyubiquitination of Prx1 and p53 in E6-independent and E6-dependent manner | Only in RaPID System cell free system | No reported applications | [55] |
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Zhang, X.; Linder, S.; Bazzaro, M. Drug Development Targeting the Ubiquitin–Proteasome System (UPS) for the Treatment of Human Cancers. Cancers 2020, 12, 902. https://doi.org/10.3390/cancers12040902
Zhang X, Linder S, Bazzaro M. Drug Development Targeting the Ubiquitin–Proteasome System (UPS) for the Treatment of Human Cancers. Cancers. 2020; 12(4):902. https://doi.org/10.3390/cancers12040902
Chicago/Turabian StyleZhang, Xiaonan, Stig Linder, and Martina Bazzaro. 2020. "Drug Development Targeting the Ubiquitin–Proteasome System (UPS) for the Treatment of Human Cancers" Cancers 12, no. 4: 902. https://doi.org/10.3390/cancers12040902