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Cyclization is a pivotal strategy for enhancing the drug-like characteristics of polypeptides. To develop potent and metabolically stable proteasome inhibitors, we generated a macrocyclic peptide skeleton using a straightforward and efficient cyclization strategy. Subsequent stability assessments confirmed the practicality of this approach. Leveraging this skeleton, we designed and synthesized a series of epoxyketone macrocyclic peptidyl proteasome inhibitors. Approximately half of these compounds showcased robust inhibitory potency, with IC 50 values below 200 nM against chymotrypsin-like (ChT-L, β5) activity. Notably, compounds 6f, 6g, and 6m demonstrated pronounced anti-proliferative activities at low nanomolar concentrations against three hematoma cell lines (RPMI-8226, RS4;11, and MV-4-11) as well as the NCI-H1299 cell line. These findings highlight the potential of these cyclic peptides to bolster the stability of proteasome inhibitors, thereby providing valuable insights for the advancement of innovative proteasome inhibitor therapies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Proteasome is vital for intracellular protein homeostasis as it eliminates misfolded and damaged protein. Inhibition of proteasome has been validated as a powerful strategy for anti-cancer therapy, and several drugs have been approved for treatment of multiple myeloma. Recent studies indicate that proteasome has potent therapeutic effects on a variety of diseases besides cancer, including parasite infectious diseases, bacterial/fungal infections diseases, neurodegenerative diseases and autoimmune diseases. In this review, recent developments of proteasome inhibitors for various diseases and related structure activity relationships are going to be summarized., Competing Interests: The authors confirm that this article content has no conflicts of interest., (© 2020 Cao et al.)

Immunoproteasome is associated with various diseases such as hematologic malignancies, inflammatory, autoimmune and central nervous system diseases, and over expression of immunoproteasome is observed in all of these diseases. Immunoproteasome inhibitors can reduce the expression of immunoproteasome by inhibiting the production of related cell-inducing factors and the activity of T lymphocyte for treating related diseases. In order to achieve good efficacy and reduce the toxic effects, key for development of selective immunoproteasome inhibitors is the high selectivity and potent activity of the three active subunits of the proteasome. This review summarizes the structure and functions of immunoproteasome and the associated diseases. Besides, structure, activity and status of selective immunoproteasome inhibitors are also been highlighted.

The immunoproteasome, a specialized form of proteasome, is mainly expressed in lymphocytes and monocytes of jawed vertebrates and responsible for the generation of antigenic peptides for cell-mediated immunity. Overexpression of immunoproteasome have been detected in a wide range of diseases including malignancies, autoimmune and inflammatory diseases. Following the successful approval of constitutive proteasome inhibitors bortezomib, carfilzomib and Ixazomib, and with the clarification of immunoproteasome crystal structure and functions, a variety of immunoproteasome inhibitors were discovered or rationally developed. Not only the inhibitory activities, the selectivities for immunoproteasome over constitutive proteasome are essential for the clinical potential of these analogues, which has been validated by the clinical evaluation of immunoproteasome-selective inhibitor KZR-616 for the treatment of systemic lupus erythematosus. In this review, structure, function as well as the current developments of various inhibitors against immunoproteasome are going to be summarized, which help to fully understand the target for drug discovery., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

[Display omitted] • A series of proteasome inhibitors incorporated with four-membered heterocycles were designed, synthesized and evaluated. • Compounds 73 exhibited excellent proteasome inhibitory activities. • Compounds 73 displayed potent antiproliferative activities against RPMI-8226 and MM-1S cell lines. • Compound 73 showed high metabolic stability in vitro. Peptides have limitations as active pharmaceutical agents due to rapid hydrolysis by proteases and poor cell permeability. To overcome these limitations, a series of peptidyl proteasome inhibitors embedded with four-membered heterocycles were designed to enhance their metabolic stabilities. All synthesized compounds were screened for their inhibitory activities against human 20S proteasome, and 12 target compounds displayed potent efficacy with IC 50 values lower than 20 nM. Additionally, these compounds exhibited strong anti-proliferative activities against multiple myeloma (MM) cell lines (MM1S: 72 , IC 50 = 4.86 ± 1.34 nM; RPMI-8226: 67 , IC 50 = 12.32 ± 1.44). Metabolic stability assessments of SGF, SIF, plasma and blood were conducted, and the representative compound 73 revealed long half-lives (Plasma: T 1/2 = 533 min; Blood: T 1/2 > 1000 min) and good proteasome inhibitory activity in vivo. These results suggest that compound 73 serve as a lead compound for the development of more novel proteasome inhibitors. [ABSTRACT FROM AUTHOR]

[Display omitted] • An overview of the structure and functions of proteasome. • Elucidate the mechanism of action of noncompetitive proteasome inhibitors and explain their advantages and disadvantages over competitive inhibitors. • A review of recently reported noncompetitive proteasome inhibitors and their mechanism of action and structure–activity relationship. • Summarize the future development direction and application prospect of noncompetitive proteasome inhibitors. The proteasome regulates intracellular processes, maintains biological homeostasis, and has shown great significance in the study of various diseases, such as neurodegenerative diseases, immune-related diseases, and cancer, especially in hematologic malignancies such as multiple myeloma (MM) and mantle cell lymphoma (MCL). All clinically used proteasome inhibitors bind to the active site of the proteasome and thus exhibit a competitive mechanism. The development of resistance and intolerance during treatment drives the search for inhibitors with different mechanisms of action. In this review, we provide an overview of noncompetitive proteasome inhibitors, including their mechanisms of action, function, possible applications, and their advantages and disadvantages compared with competitive inhibitors. [ABSTRACT FROM AUTHOR]

A series of novel non-covalent peptidomimetic proteasome inhibitors possessing bulky group at the C-terminus and N -alkylation at the N -terminus were designed with the aim to increase metabolic stabilities in vivo. All the target compounds were screened for their inhibitory activities against human 20S proteasome, and most analogs exhibited notable potency compared with the positive control bortezomib with IC 50 values lower than 10 nM, which also displayed potent cytotoxic activities against multiple myeloma (MM) cell lines and human acute myeloid leukemia (AML) cells. Furthermore, whole blood stability and in vivo proteasome inhibitory activity experiments of selected compounds were conducted for further evaluation, and the representative compound 43 (IC 50 = 8.39 ± 2.32 nM, RPMI-8226: IC 50 = 15.290 ± 2.281 nM, MM-1S: IC 50 = 9.067 ± 3.103 nM, MV-4-11: IC 50 = 2.464 ± 0.713 nM) revealed a half-life extension of greater than 9-fold (329.21 min VS 36.79 min) and potent proteasome inhibitory activity in vivo. The positive results confirmed the reliability of the metabolism guided optimization strategy, and the analogs discovered are potential leads for exploring new anti -MM drugs. [Display omitted] • A series of non-covalent proteasome inhibitors with bulky group and N -alkylation were synthesized and evaluated. • Compounds 43 and 53 exhibited excellent proteasome inhibitory activities. • Compounds 43 and 53 displayed potent antiproliferative activities against RPMI-8226, MM-1S and MV-4-11 cell lines. • Compound 43 showed high metabolic stability in vitro. [ABSTRACT FROM AUTHOR]