Immunoproteasome-selective inhibitors: An overview of recent developments as potential drugs for hematologic malignancies and autoimmune diseases

Xi, Jianjun; Zhuang, Ran; Kong, Limin; He, Ruoyu; Zhu, Huajian; Zhang, Jiankang

doi:10.1016/j.ejmech.2019.111646

Cited by 32 publications

(36 citation statements)

References 103 publications

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“…Most inhibitors of the constitutive proteasomes, such as the 20S CP inhibitors Bortezomib, Carfilzomib and Ixazomib are non-selective immunoproteasome inhibitors [256]. For example, the inhibitory activity of Bortezomib against proteasome β5c is IC50 7nM and against immunoproteasome β5i is IC50 3.3nM [257].…”

Section: Non-selective Inhibitors Of Immunoproteasomementioning

confidence: 99%

“…PR-924 is another tripeptide epoxyketone immunoproteasome β5i-selective inhibitor. As compared to ONX-0914, PR-924 displayed a much stronger inhibitory activity towards immunoproteasome (IC50 2.5 nM) compared to the constitutive proteasome β5c subunit (IC50 227 nM) [256]. PR-924 was shown to inhibit the growth of multiple myeloma cells in vitro and in vivo with no significant side effects on normal peripheral blood mononuclear cells [167].…”

Section: Pr-924mentioning

confidence: 99%

“…KZR-616 is currently the only immunoproteasome-selective inhibitor that was approved by the FDA and tested in clinic [168]. It is worth noting that the derivatives of KZR-616 also display an improved inhibitory activity towards the β1i subunit of immunoproteasome, with an IC50 0.425 nM towards β1i, but an IC50 > 250 nM towards β1c (β5c/β5i > 602) [256].…”

Section: Kzr-616mentioning

confidence: 99%

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Drug Development Targeting the Ubiquitin–Proteasome System (UPS) for the Treatment of Human Cancers

Zhang

Linder

Bazzaro

2020

Cancers

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Cancer cells are characterized by a higher rate of protein turnover and greater demand for protein homeostasis compared to normal cells. In this scenario, the ubiquitin-proteasome system (UPS), which is responsible for the degradation of over 80% of cellular proteins within mammalian cells, becomes vital to cancer cells, making the UPS a critical target for the discovery of novel cancer therapeutics. This review systematically categorizes all current reported small molecule inhibitors of the various essential components of the UPS, including ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), ubiquitin ligases (E3s), the 20S proteasome catalytic core particle (20S CP) and the 19S proteasome regulatory particles (19S RP), as well as their mechanism/s of action and limitations. We also discuss the immunoproteasome which is considered as a prospective therapeutic target of the next generation of proteasome inhibitors in cancer therapies.Cancers 2020, 12, 902 2 of 34 core component of the nucleosome, which is critical for transcription and cell cycle, is recognized and linked by Lysine Residue 48 (K48) and further degraded by the proteasome [17,18]; DbpB (also named Y-box protein 1), a transcription factor, is reported to selectively recognize the Y-box promoter element. Studies showed that its terminal 105-amino-acid-long fragment is removed after a specific proteolytic cleavage by the proteasome complex [19,20]; NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is located outside the nucleus and is reported to be involved in DNA transcription as well as cell survival [21,22]. The NF-κB p105 is the precursor of NF-κB p50. It is evident that NF-κB p105 is cleaved and selectively degraded at the C-terminus by proteasome, generating the active form of NF-κB p50 [23]. Products of UPS degradation can also be further degraded into single amino acids by aminopeptidases [24]. Aminopeptidases are the class of enzymes that catalyze the final steps in the ubiquitin-proteasome pathway by breaking down shorter peptides (<5 residues) into even smaller fragments [25]. Many, but not all, of aminopeptidases, are zinc metalloenzymes, such as leucine aminopeptidases (lAPs) and methionine aminopeptidases (metAPs) [26,27]. Studies showed that blocking the activity of the aminopeptidases by inhibitor of bestatin could generate a major accumulation of peptides which are ∼2-5 residues long [28].The 26S proteasome contains one/two 19S regulatory particles (19S RP) which mainly regulate the translocation of ubiquitinated proteins to the 20S CP and one 20S core particle (20S CP) in which proteolysis finally occurs [29,30]. In general, two main processes are associated with the process of degradation of proteins by the UPS: (1) tagging the to-be-degraded proteins by polyubiquitination (normally more than four ubiquitins), and (2) proteolytic degradation of the polyubiquitinated protein by the 26S proteasome complex [31,32]. Each step incorporates an intricate and complex spectrum of protein interaction...

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Section: Non-selective Inhibitors Of Immunoproteasomementioning

confidence: 99%

Section: Pr-924mentioning

confidence: 99%

Section: Kzr-616mentioning

confidence: 99%

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Drug Development Targeting the Ubiquitin–Proteasome System (UPS) for the Treatment of Human Cancers

Zhang

Linder

Bazzaro

2020

Cancers

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“…The increasing evidence of the role of IP in inflammation and neurodegenerative diseases has raised the interest to target the IP for therapy. Several IP inhibitors have been developed for autoimmune diseases and some cancers [ 175 ]. Currently, KZR-616 inhibitor from Kezar Life Sciences is being tested in a clinical trial for Systemic Lupus Erythematosus with and without Nephritis (ClinicalTrials.gov Identifier: NCT03393013).…”

Section: Immunoproteasome and Neuroinflammation In Neurodegeneratimentioning

confidence: 99%

Proteostasis Disturbances and Inflammation in Neurodegenerative Diseases

Sonninen

Goldsteins

Laham-Karam

et al. 2020

Cells

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Protein homeostasis (proteostasis) disturbances and inflammation are evident in normal aging and some age-related neurodegenerative diseases. While the proteostasis network maintains the integrity of intracellular and extracellular functional proteins, inflammation is a biological response to harmful stimuli. Cellular stress conditions can cause protein damage, thus exacerbating protein misfolding and leading to an eventual overload of the degradation system. The regulation of proteostasis network is particularly important in postmitotic neurons due to their limited regenerative capacity. Therefore, maintaining balanced protein synthesis, handling unfolding, refolding, and degrading misfolded proteins are essential to preserve all cellular functions in the central nervous sysytem. Failing proteostasis may trigger inflammatory responses in glial cells, and the consequent release of inflammatory mediators may lead to disturbances in proteostasis. Here, we review the mechanisms of proteostasis and inflammatory response, emphasizing their role in the pathological hallmarks of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Furthermore, we discuss the interplay between proteostatic stress and excessive immune response that activates inflammation and leads to dysfunctional proteostasis.

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“…Seven distinct α-subunits (α1-α7) form the two outer α-rings and the two inner rings possess seven different β-subunits (β1-β7) [17]. The proteolytic activity resides in β1, β2, and β5 subunits, which are responsible for the caspase-like (C-L), trypsin-like (T-L), and chymotrypsin-like (ChT-L) activities, respectively [18]. Under the stimuli of certain pro-inflammatory cytokines such as interferon (IFN)-γ and tumor necrosis factor (TNF)-α, the β1, β2, and β5 subunits are replaced by functionally different counterparts named β1i (low molecular mass polypeptide 2, LMP2), β2i (multicatalytic endopeptidase complex-like-1, MECL-1) and β5i (LMP7), forming the variant immunoproteasome [19].…”

Section: Structure and Activity Of The (Immuno) Proteasomementioning

confidence: 99%

Immunoproteasome in IgA Nephropathy: State-of-Art and Future Perspectives

Gan

Zhou³

et al. 2020

Int. J. Biol. Sci.

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IgA nephropathy (IgAN) is a leading cause of chronic kidney disease and renal failure. The exact pathogenesis of IgAN is not well defined, but some genetic studies have led to a novel discovery that the immunoproteasome probably plays an important role in IgAN. The immunoproteasome is a proteasome variant that is expressed when cells are stressed or receive inflammatory signals. While immunoproteasome is suggested to be mainly involved in major histocompatibility complex-I (MHC-I) antigen presentation, recent studies indicate that it may assert broad functions in trafficking events that activate both innate and adaptive immunity. In this review, we first summarize new insights into its functions in immunity, and discuss how it underlies its associations with IgAN. We also highlight its potential as a therapeutic target for the future.

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Immunoproteasome-selective inhibitors: An overview of recent developments as potential drugs for hematologic malignancies and autoimmune diseases

Cited by 32 publications

References 103 publications

Drug Development Targeting the Ubiquitin–Proteasome System (UPS) for the Treatment of Human Cancers

Drug Development Targeting the Ubiquitin–Proteasome System (UPS) for the Treatment of Human Cancers

Proteostasis Disturbances and Inflammation in Neurodegenerative Diseases

Immunoproteasome in IgA Nephropathy: State-of-Art and Future Perspectives

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