Required Immunoproteasome Subunit Inhibition Profile for Anti-Inflammatory Efficacy and Clinical Candidate KZR-616 ((2S,3R)-N-((S)-3-(Cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)-3-hydroxy-3-(4-methoxyphenyl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propenamide)

Johnson, Henry W. B.; Lowe, Eric; Anderl, Janet L.; Fan, Andrea; Muchamuel, Tony; Bowers, Simeon; Moebius, David C.; Kirk, Christopher J.; McMinn, Dustin L.

doi:10.1021/acs.jmedchem.8b01201

Cited by 72 publications

(89 citation statements)

References 28 publications

(91 reference statements)

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“…The only epoxyketone-based peptidyl immunoproteasome selective inhibitor tested in clinic so far Systemic lupus erythematosus (NCT03393013) [168]…”

Section: Pr-924 β5imentioning

confidence: 99%

“…KZR-616 is the third tripeptide epoxyketone immunoproteasome-selective inhibitor developed based on the optimization of the inhibitors ONX-0914 and PR-924. 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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“…The only epoxyketone-based peptidyl immunoproteasome selective inhibitor tested in clinic so far Systemic lupus erythematosus (NCT03393013) [168]…”

Section: Pr-924 β5imentioning

confidence: 99%

Section: Kzr-616mentioning

confidence: 99%

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

Zhang

Linder

Bazzaro

2020

Cancers

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“…KZR-616 is the only immunoproteasome inhibitor that has advanced to the stage of clinical trials [141]. It was developed on the basis of ONX0914, an epoxyketone that selectively inhibits the β5i subunit with an IC 50 of~39 nM (Figure 2 and Table 2) [142].…”

Section: Kzr-616mentioning

confidence: 99%

“…ONX0914 has shown efficacy in animal models of autoimmune disorders without affecting normal immune function [143,144]. Compared to ONX0914, KZR-616 has improved solubility and shows better efficacy in mouse models of antibody-induced arthritis [141]. It is in clinical testing to treat autoimmune diseases [141], expanding the indications of proteasome inhibitors beyond cancer.…”

Section: Kzr-616mentioning

confidence: 99%

“…Compared to ONX0914, KZR-616 has improved solubility and shows better efficacy in mouse models of antibody-induced arthritis [141]. It is in clinical testing to treat autoimmune diseases [141], expanding the indications of proteasome inhibitors beyond cancer. Notably, a second immunoproteasome inhibitor, M3258, targeting β5i was disclosed and will be tested in combination with dexamethasone in an upcoming phase I clinical trial for treating MM [145].…”

Section: Kzr-616mentioning

confidence: 99%

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Proteasome Inhibitors: Harnessing Proteostasis to Combat Disease

Sherman

Li²

2020

Molecules

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The proteasome is the central component of the main cellular protein degradation pathway. During the past four decades, the critical function of the proteasome in numerous physiological processes has been revealed, and proteasome activity has been linked to various human diseases. The proteasome prevents the accumulation of misfolded proteins, controls the cell cycle, and regulates the immune response, to name a few important roles for this macromolecular “machine.” As a therapeutic target, proteasome inhibitors have been approved for the treatment of multiple myeloma and mantle cell lymphoma. However, inability to sufficiently inhibit proteasome activity at tolerated doses has hampered efforts to expand the scope of proteasome inhibitor-based therapies. With emerging new modalities in myeloma, it might seem challenging to develop additional proteasome-based therapies. However, the constant development of new applications for proteasome inhibitors and deeper insights into the intricacies of protein homeostasis suggest that proteasome inhibitors might have novel therapeutic applications. Herein, we summarize the latest advances in proteasome inhibitor development and discuss the future of proteasome inhibitors and other proteasome-based therapies in combating human diseases.

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Immunoproteasome

Kimura¹

2020

Encyclopedia of Life Sciences

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The immunoproteasome is a proteolytic complex whose five subunits, β1i, β2i, β5i, PA28α and PA28β, are replaced with subunits in the constitutive proteasome. It plays an important role in the immune system and the pathogenesis of inflammatory diseases. In addition, the immunoproteasome regulates the polarisation of immune cells such as M2 macrophages and Th1 and Th17 lymphocytes. While expression of the immunoproteasome is dominant in haematopoietic cells, nonhaematopoietic cells in various peripheral tissues also express the immunoproteasome, and its expression is enhanced by inflammatory cytokines and stress signals. Recent studies indicate that each subunit of the immunoproteasome plays a unique role in nonhaematopoietic cells. For instance, β5i plays a critical role in adipogenesis and metabolic disorders. Furthermore, genetical mutation of the immunoproteasome subunits causes autoinflammatory diseases and lipodystrophy. Key Concepts The immunoproteasome plays an important role in the immune system. The immunoproteasome is involved in the pathogenesis of inflammatory diseases. Inhibition of the immunoproteasome is useful as a treatment for inflammatory diseases and tumours. The immunoproteasome plays a unique role in nonhaematopoietic cells. Deficiency of the immunoproteasome influences endocrine metabolic functions. Mutation of the immunoproteasome subunit is associated with autoinflammatory diseases and lipodystrophy.

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Required Immunoproteasome Subunit Inhibition Profile for Anti-Inflammatory Efficacy and Clinical Candidate KZR-616 ((2S,3R)-N-((S)-3-(Cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)-3-hydroxy-3-(4-methoxyphenyl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propenamide)

Cited by 72 publications

References 28 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

Proteasome Inhibitors: Harnessing Proteostasis to Combat Disease

Immunoproteasome

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