Targeting the Ubiquitin–Proteasome System for Cancer

Abstract

Ubiquitin is a highly conserved small molecule that exists in large quantities in eukaryotic cells and plays a crucial role in protein quality control by phagocytosis and degradation of ubiquitin-modified proteins. The abnormal expression of the ubiquitin–proteasome system (UPS) in cancer leads to the abnormal expression of ubiquitin ligases and ubiquitin-binding enzymes, resulting in the abnormal accumulation of ubiquitinated proteins. Consequently, UPS dysregulation can contribute to tumor initiation, progression, and resistance to therapy. While proteasome inhibitors have shown clinical success, comprehensive reviews integrating upstream UPS components and their therapeutic potential are lacking. This paper reviews the composition of the UPS, its tumor-promoting mechanisms, as well as the small molecule inhibitors and proteasome inhibitors based on this system, including their mechanisms of action and adverse effects, and explores their clinical advances in the treatment of cancer. This review provides a valuable framework for developing next-generation anti-cancer therapies and establishes the UPS as a critical therapeutic target for precision oncology.

Keywords

ubiquitin / ubiquitin–protease / ubiquitination

References

[1] N. Nakamura, “Ubiquitin System,” International Journal of Molecular Sciences 19, no. 4 (2018): 1080.

[2] D. Popovic, D. Vucic, and I. Dikic, “Ubiquitination in Disease Pathogenesis and Treatment,” Nature Medicine 20, no. 11 (2014): 1242-1253.

[3] G. Kleiger and T. Mayor, “Perilous Journey: A Tour of the Ubiquitin-Proteasome System,” Trends in Cell Biology 24, no. 6 (2014): 352-359.

[4] S. Shaid, C. H. Brandts, H. Serve, and I. Dikic, “Ubiquitination and Selective Autophagy,” Cell Death and Differentiation 20, no. 1 (2013): 21-30.

[5] N. Snyder and G. Silva, “Deubiquitinating Enzymes (DUBs): Regulation, Homeostasis, and Oxidative Stress Response,” Journal of Biological Chemistry 297, no. 3 (2021): 101077.

[6] T. Zou and Z. Lin, “The Involvement of Ubiquitination Machinery in Cell Cycle Regulation and Cancer Progression,” International Journal of Molecular Sciences 22, no. 11 (2021): 5754.

[7] Y. Wang, S. Li, and W. Wang, “The Ubiquitin-Proteasome System in the Tumor Immune Microenvironment: A Key Force in Combination Therapy,” Frontiers in immunology 15 (2024): 1436174.

[8] S. Lub, K. Maes, E. Menu, E. De Bruyne, K. Vanderkerken, and E. Van Valckenborgh, “Novel Strategies to Target the Ubiquitin Proteasome System in Multiple Myeloma,” Oncotarget 7, no. 6 (2016): 6521-6537.

[9] S. Gandolfi, J. P. Laubach, T. Hideshima, D. Chauhan, K. C. Anderson, and P. G. Richardson, “The Proteasome and Proteasome Inhibitors in Multiple Myeloma,” Cancer and Metastasis Reviews 36, no. 4 (2017): 561-584.

[10] S. Ibrahim, M. Umer Khan, I. Khurram, et al., “Navigating PROTACs in Cancer Therapy: Advancements, Challenges, and Future Horizons,” Food Science & Nutrition 13, no. 2 (2025): e70011.

[11] F. Liu, J. Chen, K. Li, et al., “Ubiquitination and Deubiquitination in Cancer: From Mechanisms to Novel Therapeutic Approaches,” Molecular Cancer 23, no. 1 (2024): 148.

[12] F. Aliabadi, B. Sohrabi, E. Mostafavi, H. Pazoki-Toroudi, and T. J. Webster, “Ubiquitin-Proteasome System and the Role of Its Inhibitors in Cancer Therapy,” Open Biology 11, no. 4 (2021): 200390.

[13] J. Tang, M. Marchand, and G. Veggiani, “Ubiquitin Engineering for Interrogating the Ubiquitin-Proteasome System and Novel Therapeutic Strategies,” Cells 12, no. 16 (2023): 2117.

[14] G. Dagar, R. Kumar, K. K. Yadav, M. Singh, and T. K. Pandita, “Ubiquitination and Deubiquitination: Implications on Cancer Therapy,” Biochim Biophys Acta Gene Regul Mech 1866, no. 4 (2023): 194979.

[15] O. Kerscher, R. Felberbaum, and M. Hochstrasser, “Modification of Proteins by Ubiquitin and Ubiquitin-Like Proteins,” Annual Review of Cell and Developmental Biology 22 (2006): 159-180.

[16] N. Mizushima, “Ubiquitin in Autophagy and Non-Protein Ubiquitination,” Nature Structural & Molecular Biology 31, no. 2 (2024): 208-209.

[17] M. Akutsu, I. Dikic, and A. Bremm, “Ubiquitin Chain Diversity at a Glance,” Journal of Cell Science 129, no. 5 (2016): 875-880.

[18] H. Huang, R. J. Lumpkin, R. W. Tsai, et al., “Ubiquitin-Specific Proximity Labeling for the Identification of E3 Ligase Substrates,” Nature Chemical Biology 20, no. 9 (2024): 1227-1236.

[19] R. Lacoursiere, D. Hadi, and G. Shaw, “Acetylation, Phosphorylation, Ubiquitination (Oh My!): Following Post-Translational Modifications on the Ubiquitin Road,” Biomolecules 12, no. 3 (2022): 467.

[20] Y. Ye and M. Rape, “Building Ubiquitin Chains: E2 Enzymes at Work,” Nature Reviews Molecular Cell Biology 10, no. 11 (2009): 755-764.

[21] K. Swatek and D. Komander, “Ubiquitin Modifications,” Cell Research 26, no. 4 (2016): 399-422.

[22] L. Crawford and A. Irvine, “Targeting the Ubiquitin Proteasome System in Haematological Malignancies,” Blood Reviews 27, no. 6 (2013): 297-304.

[23] J. A. Harrigan, X. Jacq, N. M. Martin, and S. P. Jackson, “Deubiquitylating Enzymes and Drug Discovery: Emerging Opportunities,” Nature Reviews Drug Discovery 17, no. 1 (2018): 57-78.

[24] M. Scheffner, U. Nuber, and J. Huibregtse, “Protein Ubiquitination Involving an E1-E2-E3 Enzyme Ubiquitin Thioester Cascade,” Nature 373, no. 6509 (1995): 81-83.

[25] Y. Li, S. Li, and H. Wu, “Ubiquitination-Proteasome System (UPS) and Autophagy Two Main Protein Degradation Machineries in Response to Cell Stress,” Cells 11, no. 5 (2022): 851.

[26] C. Pohl and I. Dikic, “Cellular Quality Control by the Ubiquitin-Proteasome System and Autophagy,” Science 366, no. 6467 (2019): 818-822.

[27] D. Morimoto and M. Shirakawa, “The Evolving World of Ubiquitin: Transformed Polyubiquitin Chains,” Biomol Concepts 7, no. 3 (2016): 157-167.

[28] M. Isaacson and H. Ploegh, “Ubiquitination, Ubiquitin-Like Modifiers, and Deubiquitination in Viral Infection,” Cell Host & Microbe 5, no. 6 (2009): 559-570.

[29] R. Damgaard, “The Ubiquitin System: From Cell Signalling to Disease Biology and New Therapeutic Opportunities,” Cell Death and Differentiation 28, no. 2 (2021): 423-426.

[30] A. Hage and R. Rajsbaum, “To TRIM or Not to TRIM: The Balance of Host-Virus Interactions Mediated by the Ubiquitin System,” Journal of General Virology 100, no. 12 (2019): 1641-1662.

[31] L. Jin, “Ubiquitin Signaling in the Immune System,” Advances in Experimental Medicine and Biology 1466 (2024): 113-122.

[32] G. Çetin, S. Klafack, M. Studencka-Turski, E. Krüger, and F. Ebstein, “The Ubiquitin-Proteasome System in Immune Cells,” Biomolecules 11, no. 1 (2021): 60.

[33] P. E. Cockram, M. Kist, S. Prakash, S. Chen, I. E. Wertz, and D. Vucic, “Ubiquitination in the Regulation of Inflammatory Cell Death and Cancer,” Cell Death and Differentiation 28, no. 2 (2021): 591-605.

[34] A. Yerlikaya, E. Kanbur, B. A. Stanley, and E. Tümer, “The Ubiquitin-Proteasome Pathway and Epigenetic Modifications in Cancer,” Anti-Cancer Agents in Medicinal Chemistry 21, no. 1 (2021): 20-32.

[35] T. Sun, Z. Liu, and Q. Yang, “The Role of Ubiquitination and Deubiquitination in Cancer Metabolism,” Molecular Cancer 19, no. 1 (2020): 146.

[36] M. Clague and S. Urbé, “Ubiquitin: Same Molecule, Different Degradation Pathways,” Cell 143, no. 5 (2010): 682-685.

[37] C. Berndsen and C. Wolberger, “New Insights Into Ubiquitin E3 Ligase Mechanism,” Nature Structural & Molecular Biology 21, no. 4 (2014): 301-307.

[38] J. A. Bard, E. A. Goodall, E. R. Greene, E. Jonsson, K. C. Dong, and A. Martin, “Structure and Function of the 26S Proteasome,” Annual Review of Biochemistry 87 (2018): 697-724.

[39] J. Zinngrebe, A. Montinaro, N. Peltzer, and H. Walczak, “Ubiquitin in the Immune System,” Embo Reports 15, no. 1 (2014): 28-45.

[40] K. Tanaka, T. Mizushima, and Y. Saeki, “The Proteasome: Molecular Machinery and Pathophysiological Roles,” Biological Chemistry 393, no. 4 (2012): 217-234.

[41] D. Finley, X. Chen, and K. Walters, “Gates, Channels, and Switches: Elements of the Proteasome Machine,” Trends in Biochemical Sciences 41, no. 1 (2016): 77-93.

[42] L. Bedford, S. Paine, P. W. Sheppard, R. J. Mayer, and J. Roelofs, “Assembly, Structure, and Function of the 26S Proteasome,” Trends in Cell Biology 20, no. 7 (2010): 391-401.

[43] R. Kyle and S. Rajkumar, “Multiple Myeloma,” Blood 111, no. 6 (2008): 2962-2972.

[44] B. Cao and X. Mao, “The Ubiquitin-Proteasomal System Is Critical for Multiple Myeloma: Implications in Drug Discovery,” American Journal of Blood Research 1, no. 1 (2011): 46-56.

[45] V. Ramakrishnan, U. Painuly, T. Kimlinger, J. Haug, S. V. Rajkumar, and S. Kumar, “Inhibitor of Apoptosis Proteins as Therapeutic Targets in Multiple Myeloma,” Leukemia 28, no. 7 (2014): 1519-1528.

[46] S. Narayanan, C. Cai, Y. G. Assaraf, et al., “Targeting the Ubiquitin-Proteasome Pathway to Overcome Anti-Cancer Drug Resistance,” Drug Resistance Updates 48 (2020): 100663.

[47] S. Olsen and C. Lima, “Structure of a Ubiquitin E1-E2 Complex: Insights to E1-E2 Thioester Transfer,” Molecular Cell 49, no. 5 (2013): 884-896.

[48] G. W. Xu, M. Ali, T. E. Wood, et al., “The Ubiquitin-Activating Enzyme E1 as a Therapeutic Target for the Treatment of Leukemia and Multiple Myeloma,” Blood 115, no. 11 (2010): 2251-2259.

[49] Y. Yang, J. Kitagaki, R. Dai, et al., “Inhibitors of Ubiquitin-Activating Enzyme (E1), a New Class of Potential Cancer Therapeutics,” Cancer Research 67, no. 19 (2007): 9472-9481.

[50] A. do Patrocinio, V. Rodrigues, and L. Guidi Magalhães, “P53: Stability From the Ubiquitin-Proteasome System and Specific 26S Proteasome Inhibitors,” ACS Omega 7, no. 5 (2022): 3836-3843.

[51] D. Michael and M. Oren, “The p53-Mdm2 Module and the Ubiquitin System,” Seminars in Cancer Biology 13, no. 1 (2003): 49-58.

[52] P. Liu and N. Xie, “RFWD2 Increases Proliferation and CDDP Resistance of Osteosarcoma Cells,” Gene 933 (2025): 148973.

[53] C. Gao, Y. Liu, J. Yu, et al., “Unraveling the Role of Ubiquitin-Conjugating Enzyme UBE2T in Tumorigenesis: A Comprehensive Review,” Cells 14, no. 1 (2024): 15.

[54] M. Scheffner, “Ubiquitin, E6-AP, and Their Role in p53 Inactivation,” Pharmacology & Therapeutics 78, no. 3 (1998): 129-139.

[55] S. Sengupta, R. Lingnurkar, T. S. Carey, et al., “The Evolutionarily Conserved C-Terminal Domains in the Mammalian Retinoblastoma Tumor Suppressor Family Serve as Dual Regulators of Protein Stability and Transcriptional Potency,” Journal of Biological Chemistry 290, no. 23 (2015): 14462-14475.

[56] T. Waku, N. Nakamura, M. Koji, et al., “NRF3-POMP-20S Proteasome Assembly Axis Promotes Cancer Development via Ubiquitin-Independent Proteolysis of p53 and Retinoblastoma Protein,” Molecular and Cellular Biology 40, no. 10 (2020): e00597-19.

[57] A. Awan, M. Osman, and O. Khan, “Ubiquitination Enzymes in Cancer, Cancer Immune Evasion, and Potential Therapeutic Opportunities,” Cells 14, no. 2 (2025): 69.

[58] J. Benanti, “Coordination of Cell Growth and Division by the Ubiquitin-Proteasome System,” Seminars in Cell & Developmental Biology 23, no. 5 (2012): 492-498.

[59] A. Hock and K. Vousden, “The Role of Ubiquitin Modification in the Regulation of p53,” Biochimica Et Biophysica Acta 1843, no. 1 (2014): 137-149.

[60] T. Devine and M. Dai, “Targeting the Ubiquitin-Mediated Proteasome Degradation of p53 for Cancer Therapy,” Current Pharmaceutical Design 19, no. 18 (2013): 3248-3262.

[61] Y. Wang, G. Yang, X. Zhang, et al., “Antitumor Effect of Anti-c-Myc Aptamer-Based PROTAC for Degradation of the c-Myc Protein,” Advanced Science (Weinheim) 11, no. 26 (2024): e2309639.

[62] F. Bassermann, R. Eichner, and M. Pagano, “The Ubiquitin Proteasome System—Implications for Cell Cycle Control and the Targeted Treatment of Cancer,” Biochimica Et Biophysica Acta 1843, no. 1 (2014): 150-162.

[63] S. Reed, “Ratchets and Clocks: The Cell Cycle, Ubiquitylation and Protein Turnover,” Nature Reviews Molecular Cell Biology 4, no. 11 (2003): 855-864.

[64] J. Qi and Z. Ronai, “Dysregulation of Ubiquitin Ligases in Cancer,” Drug Resistance Updates 23 (2015): 1-11.

[65] P. Masdehors, H. Merle-Béral, K. Maloum, S. Ömura, H. Magdelénat, and J. Delic, “Deregulation of the Ubiquitin System and p53 Proteolysis Modify the Apoptotic Response in B-CLL Lymphocytes,” Blood 96, no. 1 (2000): 269-274.

[66] F. Yang, Y. A. R. Mahaman, B. Zhang, et al., “C9orf72 poly-PR Helps p53 Escape From the Ubiquitin-Proteasome System and Promotes Its Stability,” Journal of Neurochemistry 166, no. 2 (2023): 389-402.

[67] R. Abbas and S. Larisch, “Killing by Degradation: Regulation of Apoptosis by the Ubiquitin-Proteasome-System,” Cells 10, no. 12 (2021): 3465.

[68] D. Ungureanu and O. Silvennoinen, “SLIM Trims STATs: Ubiquitin E3 Ligases Provide Insights for Specificity in the Regulation of Cytokine Signaling,” Science STKE 2005, no. 304 (2005): pe49.

[69] J. Wei, Y. Yuan, C. Jin, et al., “The Ubiquitin Ligase TRAF6 Negatively Regulates the JAK-STAT Signaling Pathway by Binding to STAT3 and Mediating Its Ubiquitination,” PLoS ONE 7, no. 11 (2012): e49567.

[70] S. Shao, D. Zhou, J. Feng, et al., “Regulation of Inflammation and Immunity in Sepsis by E3 Ligases,” Frontiers in Endocrinology (Lausanne) 14 (2023): 1124334.

[71] S. Barghout and A. Schimmer, “E1 Enzymes as Therapeutic Targets in Cancer,” Pharmacological Reviews 73, no. 1 (2021): 1-58.

[72] A. Schäfer, M. Kuhn, and H. Schindelin, “Structure of the Ubiquitin-Activating Enzyme Loaded With Two Ubiquitin Molecules,” Acta crystallographica Section D, Biological crystallography 70, no. Pt 5 (2014): 1311-1320.

[73] T. Kiziltepe, K. C Anderson, J. L Kutok, et al., “JS-K Has Potent Anti-Angiogenic Activity in Vitro and Inhibits Tumour Angiogenesis in a Multiple Myeloma Model in Vivo,” Journal of Pharmacy and Pharmacology 62, no. 1 (2010): 145-151.

[74] J. Liao, X. Yang, Q. Lin, et al., “Inhibition of the Ubiquitin-Activating Enzyme UBA1 Suppresses Diet-Induced Atherosclerosis in Apolipoprotein E-Knockout Mice,” Journal of Immunology Research 2020 (2020): 7812709.

[75] M. Gundogdu and H. Walden, “Structural Basis of Generic Versus Specific E2-RING E3 Interactions in Protein Ubiquitination,” Protein Science 28, no. 10 (2019): 1758-1770.

[76] M. D Stewart, T. Ritterhoff, R. E Klevit, and P. S Brzovic, “E2 Enzymes: More Than Just Middle Men,” Cell Research 26, no. 4 (2016): 423-440.

[77] Z. Qin, B. Cui, J. Jin, et al., “The Ubiquitin-Activating Enzyme E1 as a Novel Therapeutic Target for the Treatment of Restenosis,” Atherosclerosis 247 (2016): 142-153.

[78] W. Xu, J. L. Lukkarila, S. R. da Silva, S. Paiva, P. T. Gunning, and A. D. Schimmer, “Targeting the Ubiquitin E1 as a Novel Anti-Cancer Strategy,” Current Pharmaceutical Design 19, no. 18 (2013): 3201-3209.

[79] D. Ungermannova, S. J. Parker, C. G. Nasveschuk, et al., “Identification and Mechanistic Studies of a Novel Ubiquitin E1 Inhibitor,” Journal of Biomolecular Screening: The Official Journal of the Society for Biomolecular Screening 17, no. 4 (2012): 421-434.

[80] Q. T. Bui, J. H. Hong, M. Kwak, J. Y. Lee, and P. C. Lee, “Ubiquitin-Conjugating Enzymes in Cancer,” Cells 10, no. 6 (2021): 1383.

[81] Z. Lv, K. A. Rickman, L. Yuan, et al., “S. pombe Uba1-Ubc15 Structure Reveals a Novel Regulatory Mechanism of Ubiquitin E2 Activity,” Molecular Cell 65, no. 4 (2017): 699-714.E6.

[82] S. van Wijk and H. Timmers, “The Family of Ubiquitin-Conjugating Enzymes (E2s): Deciding Between Life and Death of Proteins,” FASEB Journal 24, no. 4 (2010): 981-993.

[83] M. Goebl, L. Goetsch, and B. Byers, “The Ubc3 (Cdc34) Ubiquitin-Conjugating Enzyme Is Ubiquitinated and Phosphorylated in Vivo,” Molecular and Cellular Biology 14, no. 5 (1994): 3022-3029.

[84] D. Chauhan, G. Li, T. Hideshima, et al., “Blockade of Ubiquitin-Conjugating Enzyme CDC34 Enhances Anti-Myeloma Activity of Bortezomib/Proteasome Inhibitor PS-341,” Oncogene 23, no. 20 (2004): 3597-3602.

[85] J. Monda and I. Cheeseman, “Dynamic Regulation of Dynein Localization Revealed by Small Molecule Inhibitors of Ubiquitination Enzymes,” Open Biology 8, no. 9 (2018): 180095.

[86] N. Gombodorj, T. Yokobori, S. Yoshiyama, et al., “Inhibition of Ubiquitin-Conjugating Enzyme E2 May Activate the Degradation of Hypoxia-Inducible Factors and, Thus, Overcome Cellular Resistance to Radiation in Colorectal Cancer,” Anticancer Research 37, no. 5 (2017): 2425-2436.

[87] M. Pulvino, Y. Liang, D. Oleksyn, et al., “Inhibition of Proliferation and Survival of Diffuse Large B-Cell Lymphoma Cells by a Small-Molecule Inhibitor of the Ubiquitin-Conjugating Enzyme Ubc13-Uev1A,” Blood 120, no. 8 (2012): 1668-1677.

[88] S. Qi, X. Guan, J. Zhang, et al., “Targeting E2 Ubiquitin-Conjugating Enzyme UbcH5c by Small Molecule Inhibitor Suppresses Pancreatic Cancer Growth and Metastasis,” Molecular Cancer 21, no. 1 (2022): 70.

[89] C. Penas, V. Ramachandran, and N. Ayad, “The APC/C Ubiquitin Ligase: From Cell Biology to Tumorigenesis,” Frontiers in Oncology 1 (2011): 60.

[90] L. Buetow and D. Huang, “Structural Insights Into the Catalysis and Regulation of E3 Ubiquitin Ligases,” Nature Reviews Molecular Cell Biology 17, no. 10 (2016): 626-642.

[91] I. Gupta, K. Singh, N. K. Varshney, and S. Khan, “Delineating Crosstalk Mechanisms of the Ubiquitin Proteasome System That Regulate Apoptosis,” Frontiers in Cell and Developmental Biology 6 (2018): 11.

[92] X. Zhang, S. Linder, and M. Bazzaro, “Drug Development Targeting the Ubiquitin-Proteasome System (UPS) for the Treatment of Human Cancers,” Cancers (Basel) 12, no. 4 (2020): 902.

[93] A. Mani and E. Gelmann, “The Ubiquitin-Proteasome Pathway and Its Role in Cancer,” Journal of Clinical Oncology 23, no. 21 (2005): 4776-4789.

[94] N. Zheng and N. Shabek, “Ubiquitin Ligases: Structure, Function, and Regulation,” Annual Review of Biochemistry 86 (2017): 129-157.

[95] Q. Zhan, J. Wang, H. Zhang, and L. Zhang, “E3 Ubiquitin Ligase on the Biological Properties of Hematopoietic Stem Cell,” Journal of Molecular Medicine (Berlin) 101, no. 5 (2023): 543-556.

[96] D. Senft, J. Qi, and Z. Ronai, “Ubiquitin Ligases in Oncogenic Transformation and Cancer Therapy,” Nature Reviews Cancer 18, no. 2 (2018): 69-88.

[97] K. Noonan and K. Colson, “Immunomodulatory Agents and Proteasome Inhibitors in the Treatment of Multiple Myeloma,” Seminars in Oncology Nursing 33, no. 3 (2017): 279-291.

[98] A. Colley, T. Brauns, A. E. Sluder, M. C. Poznansky, and Y. Gemechu, “Immunomodulatory Drugs: A Promising Clinical Ally for Cancer Immunotherapy,” Trends in Molecular Medicine 30, no. 8 (2024): 765-780.

[99] M. Moschetta, Y. Kawano, and K. Podar, “Targeting the Bone Marrow Microenvironment,” Cancer Treatment and Research 169 (2016): 63-102.

[100] P. Leone, A. G. Solimando, E. Malerba, et al., “Actors on the Scene: Immune Cells in the Myeloma Niche,” Frontiers in Oncology 10 (2020): 599098.

[101] L. Sedlarikova, L. Kubiczkova, S. Sevcikova, and R. Hajek, “Mechanism of Immunomodulatory Drugs in Multiple Myeloma,” Leukemia Research 36, no. 10 (2012): 1218-1224.

[102] H. Hata, “Treatment of Multiple Myeloma by Immunomodulatory Drugs,” Rinsho Ketsueki. Japanese Journal of Clinical Hematology 52, no. 10 (2011): 1485-1495.

[103] M. Cetin, S. Buyukberber, M. Demir, et al., “Overexpression of Cyclooxygenase-2 in Multiple Myeloma: Association With Reduced Survival,” American Journal of Hematology 80, no. 3 (2005): 169-173.

[104] A. Kardosh, N. Soriano, Y. Liu, et al., “Multitarget Inhibition of Drug-Resistant Multiple Myeloma Cell Lines by Dimethyl-Celecoxib (DMC), a Non-COX-2 Inhibitory Analog of Celecoxib,” Blood 106, no. 13 (2005): 4330-4338.

[105] I. Saltarella, C. Altamura, C. Campanale, et al., “Anti-Angiogenic Activity of Drugs in Multiple Myeloma,” Cancers (Basel) 15, no. 7 (2023): 1990.

[106] A. Heine, S. A. E. Held, A. Bringmann, T. A. W. Holderried, and P. Brossart, “Immunomodulatory Effects of Anti-Angiogenic Drugs,” Leukemia 25, no. 6 (2011): 899-905.

[107] M. Bolzoni, P. Storti, S. Bonomini, et al., “Immunomodulatory Drugs Lenalidomide and Pomalidomide Inhibit Multiple Myeloma-Induced Osteoclast Formation and the RANKL/OPG Ratio in the Myeloma Microenvironment Targeting the Expression of Adhesion Molecules,” Experimental Hematology 41, no. 4 (2013): 387-397.e1.

[108] H. Quach, D. Ritchie, A. K. Stewart, et al., “Mechanism of Action of Immunomodulatory Drugs (IMiDS) in Multiple Myeloma,” Leukemia 24, no. 1 (2010): 22-32.

[109] G. H Jackson, F. E Davies, C. Pawlyn, et al., “Lenalidomide Maintenance Versus Observation for Patients With Newly Diagnosed Multiple Myeloma (Myeloma XI): A Multicentre, Open-Label, Randomised, Phase 3 Trial,” Lancet Oncology 20, no. 1 (2019): 57-73.

[110] T. Ito, H. Ando, T. Suzuki, et al., “Identification of a Primary Target of Thalidomide Teratogenicity,” Science 327, no. 5971 (2010): 1345-1350.

[111] N. J. Bahlis, D. S. Siegel, G. J. Schiller, et al., “Pomalidomide, Dexamethasone, and Daratumumab Immediately After Lenalidomide-Based Treatment in Patients With Multiple Myeloma: Updated Efficacy, Safety, and Health-Related Quality of Life Results From the Phase 2 MM-014 Trial,” Leukemia & Lymphoma 63, no. 6 (2022): 1407-1417.

[112] R. J. D'Amato, M. S. Loughnan, E. Flynn, and J. Folkman, “Thalidomide Is an Inhibitor of Angiogenesis,” PNAS 91, no. 9 (1994): 4082-4085.

[113] N. Vargesson and T. Stephens, “Thalidomide: History, Withdrawal, Renaissance, and Safety Concerns,” Expert Opinion on Drug Safety 20, no. 12 (2021): 1455-1457.

[114] L. Fricker, “Proteasome Inhibitor Drugs,” Annual Review of Pharmacology and Toxicology 60 (2020): 457-476.

[115] P. Moreau, T. Masszi, N. Grzasko, et al., “Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma,” New England Journal of Medicine 374, no. 17 (2016): 1621-1634.

[116] G. Fouquet, C. Bories, S. Guidez, et al., “Pomalidomide for Multiple Myeloma,” Expert Review of Hematology 7, no. 6 (2014): 719-731.

[117] M. Engelhardt, S. Ajayi, H. Reinhardt, S. J. Müller, S. M. Dold, and R. Wäsch, “Pomalidomide,” Recent Results in Cancer Research 212 (2018): 169-185.

[118] S. Hoy, “Pomalidomide: A Review in Relapsed and Refractory Multiple Myeloma,” Drugs 77, no. 17 (2017): 1897-1908.

[119] A. Chari, A. Suvannasankha, J. W. Fay, et al., “Daratumumab Plus Pomalidomide and Dexamethasone in Relapsed and/or Refractory Multiple Myeloma,” Blood 130, no. 8 (2017): 974-981.

[120] C. Mo and P. Richardson, “Pomalidomide in Lenalidomide-Refractory Multiple Myeloma: Far From Futile,” British Journal of Haematology 188, no. 4 (2020): 483-485.

[121] S. Zeng, W. Huang, X. Zheng, et al., “Proteolysis Targeting Chimera (PROTAC) in Drug Discovery Paradigm: Recent Progress and Future Challenges,” European Journal of Medicinal Chemistry 210 (2021): 112981.

[122] D. Nalawansha and C. Crews, “PROTACs: An Emerging Therapeutic Modality in Precision Medicine,” Cell Chemical Biology 27, no. 8 (2020): 998-1014.

[123] M. Békés, D. Langley, and C. Crews, “PROTAC Targeted Protein Degraders: The Past Is Prologue,” Nature Reviews Drug Discovery 21, no. 3 (2022): 181-200.

[124] X. Li and Y. Song, “Proteolysis-Targeting Chimera (PROTAC) for Targeted Protein Degradation and Cancer Therapy,” Journal of Hematology & Oncology 13, no. 1 (2020): 50.

[125] N. Guedeney, M. Cornu, F. Schwalen, C. Kieffer, and A. S. Voisin-Chiret, “PROTAC Technology: A New Drug Design for Chemical Biology With Many Challenges in Drug Discovery,” Drug Discovery Today 28, no. 1 (2023): 103395.

[126] O. A. Koroleva, Y. V. Dutikova, A. V. Trubnikov, et al., “PROTAC: Targeted Drug Strategy. Principles and Limitations,” Russian Chemical Bulletin 71, no. 11 (2022): 2310-2334.

[127] T. Li, S. Hogenhout, and W. Huang, “Ubiquitin-Independent Degradation: An Emerging PROTAC Approach?” BioEssays 47, no. 2 (2025): e202400161.

[128] S. L. Lim, A. Damnernsawad, P. Shyamsunder, et al., “Proteolysis Targeting Chimeric Molecules as Therapy for Multiple Myeloma: Efficacy, Biomarker and Drug Combinations,” Haematologica 104, no. 6 (2019): 1209-1220.

[129] J. Lu, Y. Qian, M. Altieri, et al., “Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4,” Chemistry & Biology 22, no. 6 (2015): 755-763.

[130] G. A. Holdgate, C. Bardelle, S. K. Berry, A. Lanne, and M. E. Cuomo, “Screening for Molecular Glues—Challenges and Opportunities,” SLAS Discovery 29, no. 2 (2024): 100136.

[131] T. Lemaitre, M. Cornu, F. Schwalen, M. Since, C. Kieffer, and A. S. Voisin-Chiret, “Molecular Glue Degraders: Exciting Opportunities for Novel Drug Discovery,” Expert Opinion on Drug Discovery 19, no. 4 (2024): 433-449.

[132] X. Tan, Z. Huang, H. Pei, Z. Jia, and J. Zheng, “Molecular Glue-Mediated Targeted Protein Degradation: A Novel Strategy in Small-Molecule Drug Development,” Iscience 27, no. 9 (2024): 110712.

[133] B. Wang, S. Cao, and N. Zheng, “Emerging Strategies for Prospective Discovery of Molecular Glue Degraders,” Current Opinion in Structural Biology 86 (2024): 102811.

[134] S. Rajkumar, “Multiple Myeloma: Every Year a New Standard?” Hematological Oncology 37, no. Suppl 1 (2019): 62-65.

[135] C. Röllig, S. Knop, and M. Bornhäuser, “Multiple Myeloma,” Lancet 385, no. 9983 (2015): 2197-2208.

[136] J. E. Park, Z. Miller, Y. Jun, W. Lee, and K. B. Kim, “Next-Generation Proteasome Inhibitors for Cancer Therapy,” Translational Research 198 (2018): 1-16.

[137] Q. Dou and J. Zonder, “Overview of Proteasome Inhibitor-Based Anti-Cancer Therapies: Perspective on Bortezomib and Second Generation Proteasome Inhibitors Versus Future Generation Inhibitors of Ubiquitin-Proteasome System,” Current Cancer Drug Targets 14, no. 6 (2014): 517-536.

[138] H. Yagi, “Proteasome Inhibitor,” Nihon Rinsho 72, no. 6 (2014): 1125-1129.

[139] J. Wu and J. Liu, “Research Progress in Proteasome Inhibitor Resistance to Multiple Myeloma,” Zhong Nan Da Xue Xue Bao Yi Xue Ban 46, no. 8 (2021): 900-908.

[140] A. T. Nunes and C. M. Annunziata, “Proteasome Inhibitors: Structure and Function,” Seminars in Oncology 44, no. 6 (2017): 377-380.

[141] G. A. Collins and A. L. Goldberg, “The Logic of the 26S Proteasome,” Cell 169, no. 5 (2017): 792-806.

[142] C. Arkinson, K. C. Dong, C. L. Gee, and A. Martin, “Mechanisms and Regulation of Substrate Degradation by the 26S Proteasome,” Nature Reviews Molecular Cell Biology 26, no. 2 (2025): 104-122.

[143] M. Wehmer and E. Sakata, “Recent Advances in the Structural Biology of the 26S Proteasome,” International Journal of Biochemistry & Cell Biology 79 (2016): 437-442.

[144] L. Budenholzer, C. L. Cheng, Y. Li, and M. Hochstrasser, “Proteasome Structure and Assembly,” Journal of Molecular Biology 429, no. 22 (2017): 3500-3524.

[145] B. Teicher and J. Tomaszewski, “Proteasome Inhibitors,” Biochemical Pharmacology 96, no. 1 (2015): 1-9.

[146] I. Sahu and M. Glickman, “Proteasome in Action: Substrate Degradation by the 26S Proteasome,” Biochemical Society Transactions 49, no. 2 (2021): 629-644.

[147] J. Park, J. Cho, and E. Song, “Ubiquitin-Proteasome System (UPS) as a Target for Anticancer Treatment,” Archives of Pharmacal Research 43, no. 11 (2020): 1144-1161.

[148] I. Livneh, V. Cohen-Kaplan, C. Cohen-Rosenzweig, N. Avni, and A. Ciechanover, “The Life Cycle of the 26S Proteasome: From Birth, Through Regulation and Function, and Onto Its Death,” Cell Research 26, no. 8 (2016): 869-885.

[149] E. Scalzulli, S. Grammatico, F. Vozella, and M. T. Petrucci, “Proteasome Inhibitors for the Treatment of Multiple Myeloma,” Expert Opinion on Pharmacotherapy 19, no. 4 (2018): 375-386.

[150] M. Unno and T. Tsukihara, “Structural Biology of Proteasome,” Tanpakushitsu Kakusan Koso 51, no. Suppl 10 (2006): 1219-1223.

[151] A. Manfredonia and D. Kraut, “The 26S Proteasome Switches Between ATP-Dependent and -Independent Mechanisms in Response to Substrate Ubiquitination,” Biomolecules 12, no. 6 (2022): 750.

[152] N. Shabek, Y. Herman-Bachinsky, S. Buchsbaum, et al., “The Size of the Proteasomal Substrate Determines Whether Its Degradation Will be Mediated by Mono- or Polyubiquitylation,” Molecular Cell 48, no. 1 (2012): 87-97.

[153] D. Chen, M. Frezza, S. Schmitt, J. Kanwar, and Q. P. Dou, “Bortezomib as the First Proteasome Inhibitor Anticancer Drug: Current Status and Future Perspectives,” Current Cancer Drug Targets 11, no. 3 (2011): 239-253.

[154] O. Sogbein, P. Paul, M. Umar, A. Chaari, V. Batuman, and R. Upadhyay, “Bortezomib in Cancer Therapy: Mechanisms, Side Effects, and Future Proteasome Inhibitors,” Life Sciences 358 (2024): 123125.

[155] T. Mujtaba and Q. Dou, “Advances in the Understanding of Mechanisms and Therapeutic Use of bortezomib,” Discovery Medicine 12, no. 67 (2011): 471-480.

[156] Bortezomib. Nihon Rinsho 2016. 74, no. Suppl 5: 304-309.

[157] B. Cvek and Z. Dvorak, “The Ubiquitin-Proteasome System (UPS) and the Mechanism of Action of Bortezomib,” Current Pharmaceutical Design 17, no. 15 (2011): 1483-1499.

[158] J. Adams and M. Kauffman, “Development of the Proteasome Inhibitor Velcade (Bortezomib),” Cancer Investigation 22, no. 2 (2004): 304-311.

[159] N. Khalesi, S. Korani, M. Korani, T. P. Johnston, and A. Sahebkar, “Bortezomib: A Proteasome Inhibitor for the Treatment of Autoimmune Diseases,” Inflammopharmacology 29, no. 5 (2021): 1291-1306.

[160] S. Yamamoto and N. Egashira, “Pathological Mechanisms of Bortezomib-Induced Peripheral Neuropathy,” International Journal of Molecular Sciences 22, no. 2 (2021): 888.

[161] G. Cengiz Seval and M. Beksac, “The Safety of Bortezomib for the Treatment of Multiple Myeloma,” Expert Opinion on Drug Safety 17, no. 9 (2018): 953-962.

[162] L. Dick and P. Fleming, “Building on Bortezomib: Second-Generation Proteasome Inhibitors as Anti-Cancer Therapy,” Drug Discovery Today 15, no. 5-6 (2010): 243-249.

[163] K. Kortuem and A. Stewart, “Carfilzomib,” Blood 121, no. 6 (2013): 893-897.

[164] M. Khan and A. Stewart, “Carfilzomib: A Novel Second-Generation Proteasome Inhibitor,” Future Oncology 7, no. 5 (2011): 607-612.

[165] D. J. Kuhn, Q. Chen, P. M. Voorhees, et al., “Potent Activity of Carfilzomib, a Novel, Irreversible Inhibitor of the Ubiquitin-Proteasome Pathway, Against Preclinical Models of Multiple Myeloma,” Blood 110, no. 9 (2007): 3281-3290.

[166] D. Dima, D. Jiang, D. J. Singh, et al., “Multiple Myeloma Therapy: Emerging Trends and Challenges,” Cancers (Basel) 14, no. 17 (2022): 4082.

[167] A. McBride, J. Klaus, and K. Stockerl-Goldstein, “Carfilzomib: A Second-Generation Proteasome Inhibitor for the Treatment of Multiple Myeloma,” American Journal of Health-System Pharmacy 72, no. 5 (2015): 353-360.

[168] S. Strifler and S. Knop, “The Role of Carfilzomib in Treatment of Newly Diagnosed Multiple Myeloma,” Future Oncology 14, no. 30 (2018): 3123-3134.

[169] A. Gozzetti, G. Papini, V. Candi, C. Z. Brambilla, S. Sirianni, and M. Bocchia, “Second Generation Proteasome Inhibitors in Multiple Myeloma,” Anti-Cancer Agents in Medicinal Chemistry 17, no. 7 (2017): 920-926.

[170] C. Touzeau, C. Antier, and P. Moreau, “Carfilzomib in Combination With Daratumumab in the Management of Relapsed Multiple Myeloma,” Future Oncology 17, no. 9 (2021): 993-998.

[171] C. Andreu-Vieyra and J. Berenson, “Carfilzomib in Multiple Myeloma,” Expert Opinion on Biological Therapy 14, no. 11 (2014): 1685-1699.

[172] K. Redic, “Carfilzomib: A Novel Agent for Multiple Myeloma,” Journal of Pharmacy and Pharmacology 65, no. 8 (2013): 1095-1096.

[173] J. Larsen and S. Kumar, “Evolving Paradigms in the Management of Multiple Myeloma: Novel Agents and Targeted Therapies,” Rare Cancers Ther 3, no. 1 (2015): 47-68.

[174] J. Steele, “Carfilzomib: A New Proteasome Inhibitor for Relapsed or Refractory Multiple Myeloma,” Journal of Oncology Pharmacy Practice: Official Publication of the International Society of Oncology Pharmacy Practitioners 19, no. 4 (2013): 348-354.

[175] D. Schlafer, K. S. Shah, E. H. Panjic, and S. Lonial, “Safety of Proteasome Inhibitors for Treatment of Multiple Myeloma,” Expert Opinion on Drug Safety 16, no. 2 (2017): 167-183.

[176] B. Muz, R. N. Ghazarian, M. Ou, M. J. Luderer, H. D. Kusdono, and A. K. Azab, “Spotlight on Ixazomib: Potential in the Treatment of Multiple Myeloma,” Drug Design, Development and Therapy 10 (2016): 217-226.

[177] S. Zanwar, J. P. Abeykoon, and P. Kapoor, “Ixazomib: A Novel Drug for Multiple Myeloma,” Expert Review of Hematology 11, no, 10 (2018): 761-771.

[178] J. Xie, N. Wan, Z. Liang, T. Zhang, and J. Jiang, “Ixazomib—the First Oral Proteasome Inhibitor,” Leukemia & Lymphoma 60, no. 3 (2019): 610-618.

[179] T. Facon, C. P. Venner, N. J. Bahlis, et al., “Oral Ixazomib, Lenalidomide, and Dexamethasone for Transplant-Ineligible Patients With Newly Diagnosed Multiple Myeloma,” Blood 137, no. 26 (2021): 3616-3628.

[180] M. Gentile, M. Offidani, E. Vigna, et al., “Ixazomib for the Treatment of Multiple Myeloma,” Expert Opinion on Investigational Drugs 24, no. 9 (2015): 1287-1298.

[181] A. Bonnet and P. Moreau, “Safety of Ixazomib for the Treatment of Multiple Myeloma,” Expert Opinion on Drug Safety 16, no. 8 (2017): 973-980.

[182] P. G. Richardson, S. Zweegman, E. K. O'Donnell, et al., “Ixazomib for the Treatment of Multiple Myeloma,” Expert Opinion on Pharmacotherapy 19, no. 17 (2018): 1949-1968.

[183] W. Romaniuk and R. Z. Orlowski, “Proteasome Inhibitors in Cancer Therapy,” Postępy Higieny i Medycyny Doświadczalnej (Online) 69 (2015): 1443-1450.

[184] P. Hari, J. V. Matous, P. M. Voorhees, et al., “Oprozomib in Patients With Newly Diagnosed Multiple Myeloma,” Blood Cancer Journal 9, no. 9 (2019): 66.

[185] J. El-Amm and I. Tabbara, “Emerging Therapies in Multiple Myeloma,” American Journal of Clinical Oncology 38, no. 3 (2015): 315-321.

[186] P. Lawasut, D. Chauhan, J. Laubach, et al., “New Proteasome Inhibitors in Myeloma,” Current Hematologic Malignancy Reports 7, no. 4 (2012): 258-266.

[187] H. Wang, F. Guan, D. Chen, Q. P. Dou, and H. Yang, “An Analysis of the Safety Profile of Proteasome Inhibitors for Treating Various Cancers,” Expert Opinion on Drug Safety 13, no. 8 (2014): 1043-1054.

[188] Y. Syed, “Selinexor-Bortezomib-Dexamethasone: A Review in Previously Treated Multiple Myeloma,” Target Oncology 18, no. 2 (2023): 303-310.

[189] A. K. Stewart, S. V. Rajkumar, M. A. Dimopoulos, et al., “Carfilzomib, Lenalidomide, and Dexamethasone for Relapsed Multiple Myeloma,” New England Journal of Medicine 372, no. 2 (2015): 142-152.

[190] M. Merz, H. Salwender, M. Haenel, et al., “Subcutaneous Versus Intravenous Bortezomib in Two Different Induction Therapies for Newly Diagnosed Multiple Myeloma: An Interim Analysis From the Prospective GMMG-MM5 Trial,” Haematologica 100, no. 7 (2015): 964-969.

[191] O. Landgren, P. Sonneveld, A. Jakubowiak, et al., “Carfilzomib With Immunomodulatory Drugs for the Treatment of Newly Diagnosed Multiple Myeloma,” Leukemia 33, no. 9 (2019): 2127-2143.

[192] A. Chari, J. Martinez-Lopez, M. Mateos, et al., “Daratumumab Plus Carfilzomib and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma,” Blood 134, no. 5 (2019): 421-431.

[193] P. Moreau, M. Dimopoulos, J. Mikhael, et al., “Isatuximab, Carfilzomib, and Dexamethasone in Relapsed Multiple Myeloma (IKEMA): A Multicentre, Open-Label, Randomised Phase 3 Trial,” Lancet 397, no. 10292 (2021): 2361-2371.

[194] H. Gao, J. Yin, C. Ji, et al., “Targeting Ubiquitin Specific Proteases (USPs) in Cancer Immunotherapy: From Basic Research to Preclinical Application,” Journal of Experimental & Clinical Cancer Research 42, no. 1 (2023): 225.

[195] T. Sommer and D. Wolf, “The Ubiquitin-Proteasome-System,” Biochimica Et Biophysica Acta 1843, no. 1 (2014): 1.

[196] D. Hoeller and I. Dikic, “Targeting the Ubiquitin System in Cancer Therapy,” Nature 458, no. 7237 (2009): 438-444.

[197] S. Chen, Y. Liu, and H. Zhou, “Advances in the Development Ubiquitin-Specific Peptidase (USP) Inhibitors,” International Journal of Molecular Sciences 22, no. 9 (2021): 4546.

[198] T. Yao, H. Xiao, H. Wang, and X. Xu, “Recent Advances in PROTACs for Drug Targeted Protein Research,” International Journal of Molecular Sciences 23, no. 18 (2022): 10328.

[199] A. Domostegui, L. Nieto-Barrado, C. Perez-Lopez, and C. Mayor-Ruiz, “Chasing Molecular Glue Degraders: Screening Approaches,” Chemical Society Reviews 51, no. 13 (2022): 5498-5517.

[200] A. Vandross, “Proteasome Inhibitor-Based Therapy for Treatment of Newly Diagnosed Multiple Myeloma,” Seminars in Oncology 44, no. 6 (2017): 381-384.

[201] K. Okazuka and T. Ishida, “Proteasome Inhibitors for Multiple Myeloma,” Japanese Journal of Clinical Oncology 48, no. 9 (2018): 785-793.

[202] C. Enenkel, “Proteasome Dynamics,” Biochimica Et Biophysica Acta 1843, no. 1 (2014): 39-46.

[203] J. Y. Shin, S. Muniyappan, N. Tran, H. Park, S. B. Lee, and B. Lee, “Deubiquitination Reactions on the Proteasome for Proteasome Versatility,” International Journal of Molecular Sciences 21, no. 15 (2020): 5312.

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