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EpoxomicinProteasome inhibitor

Epoxomicin

Catalog No. BCC1235
Size Price Stock
10mM (in 1mL DMSO) $500.00 In stock
1mg $135.00 In stock
5mg $400.00 In stock
20mg $1,200.00 In stock
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Quality Control of Epoxomicin

Chemical structure

Epoxomicin

Biological Activity of Epoxomicin

Description Epoxomicin is a selective and irreversible inhibitor of 20S proteasome with an IC50 value of 4 nM.
Targets 20S proteasome          
IC50 4 nM          

Protocol

Cell experiment:[1]

Cell lines

HEK293T cells

Preparation method

The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months.

Reacting condition

Incubated at 0.2 μM or 2 μM epoxomicin for 1 hour

Applications

Peptides were degraded by proteasome from cytosolic, mitochondrial, and nuclear proteins. Epoxomicin is a proteasome inhibitor. It decreased the levels of the majority of intracellular peptides, companying with inhibition of the proteasome beta-2 and beta-5 subunits in HEK293T cells.

Animal experiment:[2]

Animal models

C57BL6

Dosage form

Epoxomicin (0.58 mg/kg) solubilized in 10% DMSO/PBS were injected i.p. daily for 6 days 

Application

Epoxomicin reduced inflammation in response to picrylchloride. Epoxomicin potently inhibited the irritant-associated inflammatory response by 95% when ear edema measurements were made 24 hr postchallenge.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

1. Fricker LD1, Gelman JS, Castro LM et al. Peptidomic analysis of HEK293T cells: effect of the proteasome inhibitor epoxomicin on intracellular peptides. J Proteome Res. 2012 Mar 2;11(3):1981-90.

2. Meng L1, Mohan R, Kwok BH et al. Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity. Proc Natl Acad Sci U S A. 1999 Aug 31;96(18):10403-8.

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Chemical Properties of Epoxomicin

Cas No. 134381-21-8 SDF Download SDF
Chemical Name (2S,3S)-2-[[(2S,3S)-2-[acetyl(methyl)amino]-3-methylpentanoyl]amino]-N-[(2S,3R)-3-hydroxy-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxobutan-2-yl]-3-methylpentanamide
SMILES CCC(C)C(C(=O)NC(C(C)O)C(=O)NC(CC(C)C)C(=O)C1(CO1)C)NC(=O)C(C(C)CC)N(C)C(=O)C
Standard InChIKey IODAWNKEPAAFFR-BWEKBLAESA-N
Standard InChI InChI=1S/C30H53N5O8/c1-11-17(5)23(33-29(42)25(18(6)12-2)35(10)20(8)37)27(40)34-24(19(7)36)28(41)32-21(13-16(3)4)26(39)31-14-22(38)30(9)15-43-30/h16-19,21,23-25,36H,11-15H2,1-10H3,(H,31,39)(H,32,41)(H,33,42)(H,34,40)/t17-,18-,19+,21-,23-,24-,25-,30+/m0/s1
Formula C28H50N4O7 M.Wt 554.7
Solubility Soluble in DMSO
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other courier with RT , or blue ice upon request.

Preparing Stock Solutions of Epoxomicin

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.8028 mL 9.0139 mL 18.0278 mL 36.0555 mL 45.0694 mL
5 mM 0.3606 mL 1.8028 mL 3.6056 mL 7.2111 mL 9.0139 mL
10 mM 0.1803 mL 0.9014 mL 1.8028 mL 3.6056 mL 4.5069 mL
50 mM 0.0361 mL 0.1803 mL 0.3606 mL 0.7211 mL 0.9014 mL
100 mM 0.018 mL 0.0901 mL 0.1803 mL 0.3606 mL 0.4507 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

Research Update of Epoxomicin

1. From epoxomicin to carfilzomib: chemistry, biology, and medical outcomes. Nat Prod Rep. 2013 May;30(5):600-4. doi: 10.1039/c3np20126k.
Abstract
Although it’s a microbial antitumor natural product deemed unfit for clinical development, epoxomicin was turned into YU-101 leading to the discovery of carfilzomin.
2. Peptidomic analysis of HEK293T cells: effect of the proteasome inhibitor epoxomicin on intracellular peptides. J Proteome Res. 2012 Mar 2;11(3):1981-90. doi: 10.1021/pr2012076. Epub 2012 Feb 16.
Abstract
Epoxomicin at 0.2 or 2 uM decreased levels of the majority of intracellular peptides in HEK294T cells through inhibition of beta-2 and beta-5 subunits of proteasome. However, degradation of proteasome through beta-1 subunit was enabled at a higher concentration of epoxomocon.
4. Evaluation of the in vitro growth-inhibitory effect of epoxomicin on Babesia parasites. Vet Parasitol. 2010 Jan 20;167(1):19-27. doi: 10.1016/j.vetpar.2009.09.049. Epub 2009 Oct 3.
Abstract
Epoxomicin is an inhibitor of proteasomal subunits that induces cell death through accumulation of ubiquinated proteins. Epoxomicin exhibited potent in vitro and in vivo inhibition against babesiosis alone or in combination with diminazene aceturate.
5. The proteasome inhibitor epoxomicin has potent Plasmodium falciparum gametocytocidal activity. Antimicrob Agents Chemother. 2009 Oct;53(10):4080-5. doi: 10.1128/AAC.00088-09. Epub 2009 Aug 3.
Abstract
Epoxomicin, a proteasome inhibitor, not only exhibited potent antimalarial activity killing malaria parasites without affecting normal cells but also inhibited oocyst production in the mosquito midgut.

Background on Epoxomicin

Epoxomicin was originally isolated from the culture medium of an Actinomycetes strain based on its in vivo antitumor activity against murine B16 melanoma. Epoxomicin is a naturally occurring selective proteasome inhibitor with anti-inflammatory activity. [1] Epoxomicin primarily inhibits the activity of CTRL (chymotrypsin-like proteasome).

The novel α-epoxy ketone moiety of Epoxomicin forms covalent bonds with residues in particular catalytic subunits of the enzyme, disabling activity. The trypsin-like and peptidyl-glutamyl peptide hydrolyzing behaviors of the proteasome were both inhibited by Epoxomicin as well (at 100 and 1,000-fold slower rates, respectively). The ubiquitin-proteasome pathway heavily regulates bone formation, and Epoxomicin was shown to increase both bone volume and bone formation rates in rodents.

Another study demonstrates that exposure to Epoxomicin and other proteasome inhibitors leads to dopaminergic cell death, producing a model of Parkinson's disease in vivo. Epoxomicin is an inhibitor of 20S Proteasome. [2]

References:
1. Meng, L; Mohan, R; Kwok, BH; Elofsson, M; Sin, N; Crews, CM (1999). "Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity". PNAS 96 (18): 10403–10408.
2. Epoxomicin, Santa Cruz Biotechnology.

References on Epoxomicin

Epoxomicin and Eponemycin Biosynthesis Involves gem-Dimethylation and an Acyl-CoA Dehydrogenase-Like Enzyme.[Pubmed: 26789439]


The α',β'-epoxyketone moiety of proteasome inhibitors confers high binding specificity to the N-terminal threonine in catalytic proteasome β-subunits. We recently identified the epoxomicin and eponemycin biosynthetic gene clusters and have now conducted isotope-enriched precursor feeding studies and comprehensive gene deletion experiments to shed further light on their biosynthetic pathways. Leucine and two methyl groups from S-adenosylmethionine were readily incorporated into the epoxyketone warhead, suggesting decarboxylation of the thioester intermediate. Formation of the α',β'-epoxyketone is likely mediated by conserved acyl-CoA dehydrogenase-like enzymes, as indicated by complete loss of epoxomicin and eponemycin production in the respective knockout mutants. Our results clarify crucial questions in the formation of epoxyketone compounds and lay the foundation for in vitro biochemical studies on the biosynthesis of this pharmaceutically important class of proteasome inhibitors.

Epoxomicin Sensitizes Resistant Osteosarcoma Cells to TRAIL Induced Apoptosis.[Pubmed: 25666501]


Osteosarcoma (OS) is the second most common primary malign bone neoplasm after multiple myeloma. Despite systemic chemotherapy, OS may give rise to local recurrences and metastases. Resistance to chemotherapy is not rare and is likely to occur in a high number of patients. Novel therapeutic approaches are required in order to efficiently treat osteosarcoma. Tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) and proteasome inhibitors (epoxomicin, MG132, bortezomib) represent new promising approaches in cancer treatment. The aim of our study is to elucidate the effects of epoxomicin alone or in combination with TRAIL in two TRAIL-resistant OS cell lines, Saos-2 and MG-63 namely. We determined the cytotoxic effects of epoxomicin and/or TRAIL on these two types of OS cells using dimethylthiazolyl 2,5 diphenyltetrazolium bromide (MTT) test and measured apoptosis markers such as pro-apoptotic Bax levels and caspase-3, -8, -9 activities. We used TUNEL assay to demonstrate apoptosis. We investigated dose and time dependent survival rates of OS cells and determined LD50 doses of epoxomicin and TRAIL on OS cell viability after 24, 48, and 72 hour incubations. Concurrent incubation with TRAIL and epoxomicin for 24 hour significantly increased caspase-3, caspase-8, caspase-9 activities and Bax protein levels. Our study demonstrated that the combination of TRAIL with epoxomicin enhances apoptosis, and overcomes TRAIL resistance, denoting promising results for OS therapy in the future.

Regulation of ubiquitin-proteasome and autophagy pathways after acute LPS and epoxomicin administration in mice.[Pubmed: 24885455]


The ubiquitin-proteasome pathway (UPP) is a major protein degradation pathway that is activated during sepsis and has been proposed as a therapeutic target for preventing skeletal muscle loss due to cachexia. Although several studies have investigated the modulation of proteasome activity in response to LPS administration, none have characterized the overall UPP response to LPS administration in the fate of proteasome inhibition.

From epoxomicin to carfilzomib: chemistry, biology, and medical outcomes.[Pubmed: 23575525]


The initial enthusiasm following the discovery of a pharmacologically active natural product is often fleeting due to the poor prospects for its ultimate clinical application. Despite this, the ever-changing landscape of modern biology has a constant need for molecular probes that can aid in our understanding of biological processes. After its initial discovery by Bristol-Myers Squibb as a microbial anti-tumor natural product, epoxomicin was deemed unfit for development due to its peptide structure and potentially labile epoxyketone pharmacophore. Despite its drawbacks, epoxomicin's pharmacophore was found to provide unprecedented selectivity for the proteasome. Epoxomicin also served as a scaffold for the generation of a synthetic tetrapeptide epoxyketone with improved activity, YU-101, which became the parent lead compound of carfilzomib (Kyprolis™), the recently approved therapeutic agent for multiple myeloma. In this era of rational drug design and high-throughput screening, the prospects for turning an active natural product into an approved therapy are often slim. However, by understanding the journey that began with the discovery of epoxomicin and ended with the successful use of carfilzomib in the clinic, we may find new insights into the keys for success in natural product-based drug discovery.

Kewords:

Epoxomicin,134381-21-8,Ubiquitination,Proteasome, supplier, inhibitor,Antagonist,Blocker,Modulator,Agonist, activators, activates, potent, BioCrick

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