![Structures of some peptide aldehydes (a). Their binding to the catalytic threonine leading to the reversible adduct 1 identified from the crystal structure of proteasome/peptide aldehydes complexes [4,40] (b). Structures of recently discovered peptide aldehydes: fellutamide B, compounds 2, 3 and IPSI-001 (c).](https://www.researchgate.net/profile/Joelle-Vidal/publication/41485610/figure/fig3/AS:667628737671170@1536186503165/Fig-5-Structures-of-some-peptide-aldehydes-a-Their-binding-to-the-catalytic_Q320.jpg)
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Proteasome Inhibitors: Recent Advances and New Perspectives In Medicinal Chemistry
Abstract and Figures
The search for proteasome inhibitors began fifteen years ago. These inhibitors proved to be powerful tools for investigating many important cellular processes regulated by the ubiquitin-proteasome pathway. Targeting the proteasome pathway can also lead to new treatments for disorders like cancer, muscular dystrophies, inflammation and immune diseases. This is already true for cancer; the FDA approved bortezomib, a potent proteasome inhibitor, for treating multiple myeloma in 2003, and mantle cell lymphoma in 2006. The chemical structures identified in some of the early proteasome inhibitors have led to the development of new anti-cancer drugs (CEP-18770, Carfilzomib, NPI-0052). All these molecules are covalent bonding inhibitors that react with the catalytic Thr1-O(gamma) of the three types of active site. This review covers recent developments in medicinal chemistry of natural and synthetic proteasome inhibitors. Advances in non-covalent inhibitors that have no reactive group will be highlighted as they should minimize side-effects. New structures and new modes of action have been recently identified that open the door to new drug candidates for treating a range of diseases.
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... The vinyl peptide derivatives have electron withdrawing groups (sulfone or ester) in the C-terminal which behave as Michael acceptors of the catalytic Thr1 hydroxyl group, promoting the formation of a covalent irreversible bond ( Figure 15) [61]. The peptide vinyl sulfones were first described by Nazif and Bogyo [62] and are characterized by their lower reactivity when compared to aldehydes. ...
... In vivo, it acts as a prodrug which is hydrolyzed at neutral pH into clasto-lactacystin-βlactone (also called omuralide) (Figure 17), which can cross the plasma membranes of mammalian cells (whereas the lactacystin form cannot) and it is covalently and irreversibly bound to the β5 subunit's Thr1, resulting in the opening of the β-lactone ring and acylation of the hydroxyl group in Thr1 ( Figure 18). Omuralide does not inhibit various serine and cysteine proteases, except for cathepsin A and cytosolic tripeptidyl peptidase II [27,28,61]. ...
Proteasome inhibitors have shown relevant clinical activity in several hematological malignancies, namely in multiple myeloma and mantle cell lymphoma, improving patient outcomes such as survival and quality of life, when compared with other therapies. However, initial response to the therapy is a challenge as most patients show an innate resistance to proteasome inhibitors, and those that respond to the therapy usually develop late relapses suggesting the development of acquired resistance. The mechanisms of resistance to proteasome inhibition are still controversial and scarce in the literature. In this review, we discuss the development of proteasome inhibitors and the mechanisms of innate and acquired resistance to their activity—a major challenge in preclinical and clinical therapeutics. An improved understanding of these mechanisms is crucial to guiding the design of new and more effective drugs to tackle these devastating diseases. In addition, we provide a comprehensive overview of proteasome inhibitors used in combination with other chemotherapeutic agents, as this is a key strategy to combat resistance.
... The results of this investigation showed that KJ9 inhibited both the β5c and the β5i subunits with K i values of 3.02 and 7.77 µM, while KJ3 inhibited the sole β5i subunit with a K i value of 3.85 µM [14]. In particular, unlike the covalent inhibitors, these designed analogues don't own an electrophilic moiety and could act as noncovalent immunoproteasome inhibitors also reducing the side effects due to the irreversible inhibition [15]. Therefore, the goal of this work was to investigate the effects of amide derivatives, KJ3 and KJ9, in an in vitro model TNF-α induced neuroinflammation in differentiated SH-SY5Y and HMC3 cells. ...
Neuroinflammation is an inflammatory response of the nervous tissue mediated by the production of cytokines, chemokines, and reactive oxygen species. Recent studies have shown that an upregulation of immunoproteasome is highly associated with various diseases and its inhibition attenuates neuroinflammation. In this context, the development of non-covalent immunoproteasome-selective inhibitors could represent a promising strategy for treating inflammatory diseases. Novel amide derivatives, KJ3 and KJ9, inhibit the β5 subunit of immunoproteasome and were used to evaluate their possible anti-inflammatory effects in an in vitro model of TNF-α induced neuroinflammation. Differentiated SH-SY5Y and microglial cells were challenged with 10 ng/mL TNF-α for 24 h and treated with KJ3 (1 µM) and KJ9 (1 µM) for 24 h. The amide derivatives showed a significant reduction of oxidative stress and the inflammatory cascade triggered by TNF-α reducing p-ERK expression in treated cells. Moreover, the key action of these compounds on the immunoproteasome was further confirmed by halting the IkB-α phosphorylation and the consequent inhibition of NF-kB. As downstream targets, IL-1β and IL-6 expression resulted also blunted by either KJ3 and KJ9. These preliminary results suggest that the effects of these two compounds during neuroinflammatory response relies on the reduced expression of pro-inflammatory targets.
... Bor bazlı ilaçlar, hem optik hem de nükleer görüntüleme için görüntüleme ajanları olarak kullanımın yanı sıra antikanser, antiviral, antibakteriyel, antifungal ve hastalığa özgü aktivitelere sahip terapötik ajanlar da dahil olmak üzere çeşitli biyomedikal uygulamalara sahip yeni bir molekül sınıfını temsil eder (24). Aktif element olarak bor içeren ve klinik kullanımda olan FDA izinli tek ilaç olan bortezomib (Velcade®), 2003 yılında multipl miyelom (MM) ve non-Hodgkins lenfoma tedavisi için bir proteazom inhibitörü olarak onaylanmıştır (30). ...
... For the latter, the covalent mode of action and the elevated reactivity of the compounds may often lead to off-target interactions. Lately, diverse new non-covalent PIs were identified ( Figure 1b) [17,[48][49][50][51][52]. Even if less widely investigated with respect to covalent inhibitors, they provide a valid and milder alternative mechanism for proteasome inhibition. ...
The ubiquitin-proteasome pathway (UPP) is the major proteolytic system in the cytosol and
nucleus of all eukaryotic cells. The role of proteasome inhibitors (PIs) as critical agents for regulating
cancer cell death has been established. Aziridine derivatives are well-known alkylating agents
employed against cancer. However, to the best of our knowledge, aziridine derivatives showing
inhibitory activity towards proteasome have never been described before. Herein we report a new
class of selective and nonPIs bearing an aziridine ring as a core structure. In vitro cell-based assays
(two leukemia cell lines) also displayed anti-proliferative activity for some compounds. In silico
studies indicated non-covalent binding mode and drug-likeness for these derivatives. Taken together,
these results are promising for developing more potent PIs.
... Au cours des deux dernières décennies, une recherche très active d'inhibiteurs sélectifs du protéasome s'est mise en place aussi bien aux niveaux universitaires qu'industriels en vue d'obtenir d'une part des outils de recherche, d'autre part des médicaments. Elle a abouti à une grande variété d'inhibiteurs qu'ils soient d'origine naturelle, issus de synthèses organiques ou de criblage de collections de molécules patrimoniales (Borrissenko & Groll, 2007 ;Genin et al., 2010 ;Gräwert & Groll, 2012 ;. Ce foisonnement de molécules a permis de passer des aldéhydes peptidiques (premiers inhibiteurs analogues d'inhibiteurs de protéases à sérine dont le bien connu et peu sélectif MG132) à des inhibiteurs du protéasome de structures diverses utilisés aujourd'hui en oncologie (Cromm & Crews, 2017 ;Manasanch & Orlowski, 2017 ;Sherman & Li, 2020 ;Tundo et al., 2020). ...
Le protéasome est la principale machinerie de dégradation des protéines pour toutes les cellules eucaryotes. Il est en effet impliqué dans une multitude de fonctions physiologiques. Ce rôle central dans l’homéostasie des protéines en fait une cible attractive pour des interventions thérapeutiques variées, des aberrations ayant été observées dans beaucoup de pathologies humaines. Le protéasome constitutif 26S (2,4 MDa) est formé de la particule catalytique 20S qui peut s’associer à une ou deux particules régulatrices 19S. Des analyses structurales remarquables ont permis de comprendre le fonctionnement de ce complexe multicatalytique et la régulation de la dégradation des protéines dépendant de l’ATP et de l’ubiquitine. Des changements conformationnels coordonnés de la particule régulatrice 19S permettent de coupler l’hydrolyse de l’ATP à la translocation du substrat protéique et de réguler l’ouverture du pore de la particule catalytique afin d’initier la dégradation itérative des protéines par les trois types de sites actifs. Une très grande variété d’inhibiteurs de ces activités a été découverte, qu’ils soient synthétiques ou d’origine naturelle, avec un premier succès en 2003 avec le bortezomib utilisé dans le traitement du myélome multiple, puis du lymphome du manteau. Une seconde génération d’inhibiteurs (carfilzomib et ixazomib) est employée en clinique. L’immunoprotéasome, distinct du protéasome constitutif et exprimé de manière prédominante dans les cellules immunitaires, se substitue au protéasome constitutif après induction par l’INF-γ et le TNF-α. Il devient actuellement une cible thérapeutique majeure pour traiter des cancers, des désordres auto-immuns et des troubles neurologiques à l’aide d’inhibiteurs spécifiques. Les protéasomes de certains microorganismes retiennent également l’attention en vue du développement d’inhibiteurs à visée thérapeutique. Enfin, l’activation du protéasome est une nouvelle approche pouvant aboutir au traitement des désordres protéotoxiques comme les neurodégénérescences.
The ubiquitin-proteasome pathway (UPP) represents the principal proteolytic apparatus in the cytosol and nucleus of all eukaryotic cells. Nowadays, proteasome inhibitors (PIs) are well-known as anticancer agents. However, although three of them have been approved by the US Food and Drug Administration (FDA) for treating multiple myeloma and mantel cell lymphoma, they present several side effects and develop resistance. For these reasons, the development of new PIs with better pharmacological characteristics is needed. Recently, noncovalent inhibitors have gained much attention since they are less toxic as compared with covalent ones, providing an alternative mechanism for solid tumors. Herein, we describe a new class of bis-homologated chloromethyl(trifluoromethyl)aziridines as selective noncovalent PIs. In silico and in vitro studies were conducted to elucidate the mechanism of action of such compounds. Human gastrointestinal absorption (HIA) and blood-brain barrier (BBB) penetration were also considered together with absorption, distribution, metabolism, and excretion (ADMET) predictions.
Angiotensin II (Ang II) induced Atrial fibrillation (AF) often accompanied with reduced ATRAP which is a negative modulator of Ang II type 1 receptor (AT1R). Melatonin can protect against AF, but the underlying molecular mechanism remains poorly understood. In this study, Ang II was used to induce AF, and AF inducibility and duration were documented telemetrically. Ang II-infused mice had a higher AF incidence, which was associated with atrial fibrosis, inflammation, and oxidative stress. Melatonin partially inhibited these effects, and enforced expression of siRNA-ATRAP in atria counteracted the beneficial role of melatonin. Specifically, melatonin inhibited expression of Ang II-induced proteasome and immunoproteasome subunits β2, β2i, β5, and β5i as well as their corresponding trypsin-like and chymotrypsin-like activities and blocked ATRAP degradation. In turn, this inhibited AT1R-mediated NF-κB signaling, transforming growth factor (TGF)-β1/Smad signaling in the atria, and thereby affected atrial remodeling and AF. Melatonin receptor inhibition by the chemical inhibitor luzindole partially inhibited the inhibitory effects of melatonin on proteasome activity and also Ang II-induced pathological changes in the atria. Overall, our study demonstrates that melatonin protects against Ang II-induced AF by inhibiting proteasome activity and stabilizing ATRAP expression, and these effects are partially dependent on melatonin receptor activation.
Bortezomib (BTZ) is the first proteasome inhibitor approved by the Food and Drug Administration. It can bind to the amino acid residues of the 26S proteasome, thereby causing the death of tumor cells. BTZ plays an irreplaceable role in the treatment of mantle cell lymphoma and multiple myeloma. Moreover, its use in the treatment of other hematological cancers and solid tumors has been investigated in numerous clinical trials and preclinical studies. Nevertheless, the applications of BTZ are limited due to its insufficient specificity, poor permeability, and low bioavailability. Therefore, in recent years, different BTZ-based drug delivery systems have been evaluated. In this review, we firstly discussed the functions of proteasome inhibitors and their mechanisms of action. Secondly, the properties of BTZ, as well as recent advances in both clinical and preclinical research, were reviewed. Finally, progress in research regarding BTZ-based nanoformulations was summarized.
Based on the interaction modes of the natural 20S proteasome inhibitors TMC-95A, we have previously discovered a dipeptide 1. To explore the SAR around compound 1, we designed and synthesized a series of dipeptides (8–38) with a fragment-based strategy. Among them, nine compounds showed significant inhibitory activities against the chymotrypsin-like activity of human 20S proteasome with IC50 values at the submicromolar level, which were comparable or even superior to the parent compound 1. Meanwhile, they displayed no significant inhibition against trypsin-like and caspase-like activities of 20S proteasome. The results suggested the feasibility to design dipeptides as novel and potent 20S proteasome inhibitors.
Animal, epidemiological and clinical studies have demonstrated the anti-tumor activity of pharmacological proteasome inhibitors and the cancer-preventive effects of green tea consumption. Previously, one of our laboratories reported that natural ester bond-containing green tea polyphenols (GTPs), such as (-)-epigallocatechin-3-gallate [(-)-EGCG] and (-)-gallocatechin-3-gallate [(-)-GCG], are potent and specific proteasome inhibitors. Another of our groups, for the first time, was able to enantioselectively synthesize (-)-EGCG as well as other analogs of this natural GTP. Our interest in designing and developing novel synthetic GTPs as proteasome inhibitors and potential cancer-preventive agents prompted our current study.
GTP analogs, (+)-EGCG, (+)-GCG, and a fully benzyl-protected (+)-EGCG [Bn-(+)-EGCG], were prepared by enantioselective synthesis. Inhibition of the proteasome or calpain (as a control) activities under cell-free conditions were measured by fluorogenic substrate assay. Inhibition of intact tumor cell proteasome activity was measured by accumulation of some proteasome target proteins (p27, I kappa B-alpha and Bax) using Western blot analysis. Inhibition of tumor cell proliferation and induction of apoptosis by synthetic GTPs were determined by G(1) arrest and caspase activation, respectively. Finally, inhibition of the transforming activity of human prostate cancer cells by synthetic GTPs was measured by a colony formation assay.
(+)-EGCG and (+)-GCG potently and specifically inhibit the chymotrypsin-like activity of purified 20S proteasome and the 26S proteasome in tumor cell lysates, while Bn-(+)-EGCG does not. Treatment of leukemic Jurkat T or prostate cancer LNCaP cells with either (+)-EGCG or (+)-GCG accumulated p27 and IkappaB-alpha proteins, associated with an increased G(1) population. (+)-EGCG treatment also accumulated the pro-apoptotic Bax protein and induced apoptosis in LNCaP cells expressing high basal levels of Bax, but not prostate cancer DU-145 cells with low Bax expression. Finally, synthetic GTPs significantly inhibited colony formation by LNCaP cancer cells.
Enantiomeric analogs of natural GTPs, (+)-EGCG and (+)-GCG, are able to potently and specifically inhibit the proteasome both, in vitro and in vivo, while protection of the hydroxyl groups on (+)-EGCG renders the compound completely inactive.
Immediately upon the discovery some ten years ago that inhibition of the proteasome in cultured cells, mostly of tumor origin, caused the programmed cell death machinery to ramp up, it became imperative to investigate proteasome inhibition as a possible treatment for human cancers. In Proteasome Inhibitors in Cancer Therapy, Julian Adams, the leader in developing the field, brings together a panel of highly experienced academic and pharmaceutical investigators to take stock of the remarkable work that has been accomplished to date, and examine emerging therapeutic possibilities for proteasome inhibitors in cancer. The topics range from a discussion of the chemistry and cell biology of the proteasome and the rationale for proteasome inhibitors in cancer to a review of current clinical trials underway. The discussion of the very empirical and practical development of rationales to test proteasome inhibitors in cancer models covers the role of the proteasome in NF-kB activation, the combining of conventional chemotherapy and radiation with proteasome inhibition, notably PS-341, new proteasome methods of inhibiting viral maturation, and the role of proteasome inhibition in the treatment of AIDS. The authors also document the development of bortezomib (Velcade™) through multicentered clinical trials in patients with relapsed and refractory myeloma to FDA approval, and describe how modern pharmacogenomic tools can be used to predict which patients will respond to such proteasome inhibitor therapy. Additional chapters on the proteasome's basic biochemistry review its mechanism in the cell cycle and apoptosis and suggest opportunities for using proteasome inhibitors to find additional medicinal targets.
Authoritative and illuminating, Proteasome Inhibitors in Cancer Therapy makes clear that proteasome inhibition should prove a fertile area for the many future discoveries that will provide relief of suffering and extend the quality of life of patients afflicted with cancer and other debilitating diseases.
The ubiquitin-proteasome pathway has emerged as a central player in the regulation of several diverse cellular processes. Here, we describe the important components of this complex biochemical machinery as well as several important cellular substrates targeted by this pathway and examples of human diseases resulting from defects in various components of the ubiquitin-proteasome pathway. In addition, this review covers the chemistry of synthetic and natural proteasome inhibitors, emphasizing their mode of actions toward the 20S proteasome. Given the importance of proteasome-mediated protein degradation in various intracellular processes, inhibitors of this pathway will continue to serve as both molecular probes of major cellular networks as well as potential therapeutic agents for various human diseases.
The proteasome is a multicatalytic enzyme complex responsible for the majority of protein degradation in cells. Traditionally believed to be a mere recycler of damaged or misfolded proteins, the proteasome’s importance in modulating cell cycle and survival pathways is now recognized. By degrading regulatory proteins, the proteasome helps to remove signals that promote transcription, cell growth, angiogenesis, and cell adhesion. Preclinical studies have found that agents that inhibit the proteasome’s activity will promote cell cycle arrest and induce apoptosis in tumor cells, thus establishing the proteasome as a promising potential target for anticancer therapy (1). This evidence has led to the examination of these compounds for the treatment of human cancer, and one such proteasome inhibitor, bortezomib (VELCADE TM , formerly PS-341, LDP-341, MLN341), has entered human clinical trials.
The first three clinical studies of bortezomib tested regimens of differing dose-intensities: once weekly for 4 wk on a 6 wk cycle (least intensive), twice weekly for 2 wk of a 3 wk cycle, and twice weekly for 4 wk of a 6 wk cycle (most intensive). From these studies, the intermediate-intensity regimen has been advanced, because it is the best tolerated but still achieves a high level of proteasome activity. Patients on this regimen treated with 1.0–1.50 mg/m2bortezomib had a reduction in proteasome activity to about 40% of baseline but recovered most activity within the 72 h period between doses. Doselimiting toxicities for this regimen were peripheral sensory neuropathy (PSN) and diarrhea. Patients with preexisting damage from prior neurotoxic chemotherapy may be more likely to develop PSN, and this possibility is being investigated in ongoing trials. Diarrhea is also adequately managed with loperamide. Notably, hematologic events in the early phase I trials were uncommon—thrombocytopenia was not dose-limiting; febrile neutropenia was rare; and hepatic, renal, and cardiotoxicity have not been noted. Given this favorable side effect profile, bortezomib may be particularly effective in combination-treatment regimens. In preclinical studies, bortezomib has shown at least an additive effect with CPT-11, gemcitabine, and docetaxel, and trials are in progress to determine the optimum dosing schedules for these combinations. In these ongoing trials, no unexpected or additive toxicities have been observed yet.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
The proteasome regulates diverse intracellular processes, including cell-cycle progression, cell adhesion and migration, apoptosis and antigen presentation: selective inhibitors of the proteasome, therefore, have great therapeutic potential for the treatment of cancer. TMC-95A–D are unique natural products and represent a new class of noncovalent, reversible, and selective proteasome inhibitors with exceptionally strong bioactivity profiles and interesting structural properties. Significant recent advances in the syntheses of these natural products have led to intense interest in the development of related compounds as potential anticancer agents: the chemistry and biology of these natural products and analogues will be described in this review article.RésuméLe protéasome étant un régulateur de nombreux processus intracellulaires tels que le cycle cellulaire, l'adhésion cellulaire, l'apoptose ou la présentation d'antigènes, des inhibiteurs sélectifs de ce complexe protéique ont un potentiel thérapeutique considérable, notamment pour le traitement de cancers. Les TMC-95A–D sont des produits naturels uniques qui représentent une nouvelle classe d'inhibiteurs non-covalents, réversibles et sélectifs du protéasome possédant un profil de bioactivité exceptionnellement prometteur ainsi qu'un squelette particulièrement intéressant. De récentes avancées pour la synthèse de ces produits naturels ont entraîné un grand intérêt pour le développement de composés dérivés en tant qu'agents anticancéreux: la chimie et la biologie de ces produits naturels et de ces analogues sont présentées dans cet article de revue.
In undergraduate level organometallic chem. courses students are usually taught that organometallic compds. are toxic and unstable in air and water. While this is true of many complexes, some are also non-toxic and stable in air and water. Indeed, bioorganometallic chem., the study of biomols. or biol. active mols. that contain at least one carbon directly bound to a metal, is a thriving subject, and air and water stability is a general pre-requisite. This interdisciplinary field is located at the borderline between chem., biochem., biol. and medicine. In this tutorial review, various aspects of bioorganometallic chem. are introduced, with the main emphasis on medicinal organometallic compds. Organometallic therapeutics for cancer, HIV and malaria and other medicinal applications are described. It is also shown how rational ligand design has led to new improved therapies much in the same way that an organometallic chemist working in catalysis will design new ligands for improved activities.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.