Epoxomicin (BU 4061T) is a naturally occurring selective proteasome inhibitor with anti-inflammatory activity. Epoxomicin covalently binds to the LMP7, X, MECL1, and Z catalytic subunits of the proteasome. Epoxomicin (BU 4061T) inhibits proteasome activity in cell growth assays with an IC50 value of 4 nM and demonstrates potent cytotoxicity against B16-F10, HCT116, and Moser solid tumor cells, as well as P388 and K562 leukemia cells with IC50 values ranging from 2-44 nM. Epoxomicin also effectively inhibits NF-kappaB activation in vitro and potently blocks in vivo inflammation in the murine ear edema assay. In contrast to peptide aldehyde proteasome inhibitors, epoxomicin does not inhibit nonproteasomal proteases such trypsin, chymotrypsin, papain, calpain, and cathepsin B at concentrations of up to 50 microM. Treatment of proliferating cells with epoxomicin results in cell death through accumulation of ubiquinated proteins.
Arch Virol. 2021 Aug;166(8):2173-2185.
Mol Cell. 2020 Nov 19;80(4):607-620.e12.
Paradoxical Mitophagy Regulation by PINK1 and TUFm
Epoxomicin purchased from AbMole
|Source||Mol Cell (2020), Figure 4, Epoxomicin (Abmole Bioscience Inc.)|
|Cell Lines||HeLa and HEK293T cell lines|
|Incubation Time||2-12 hours|
|Results||CCCP treatment induced accumulation of mitochondrion-localized fulllength PINK1 protein and an enhanced p-S222-TUFm signal;applying the proteasome inhibitor MG132 or epoxomicin elevated cytosolic and mitochondrial cleaved PINK1 and the p-S222-TUFm signal, and so did the autophagosome formation inhibitors CK636 and Baf-A1, but to a lesser extent|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
|Solubility||DMSO 10 mg/mL|
Evaluation of the in vitro growth-inhibitory effect of epoxomicin on Babesia parasites.
Aboulaila M, et al. Vet Parasitol. 2010 Jan 20;167(1):19-27. PMID: 19896277.
The proteasome inhibitor epoxomicin has potent Plasmodium falciparum gametocytocidal activity.
Czesny B, et al. Antimicrob Agents Chemother. 2009 Oct;53(10):4080-5. PMID: 19651911.
The selective proteasome inhibitors lactacystin and epoxomicin can be used to either up- or down-regulate antigen presentation at nontoxic doses.
Schwarz K, et al. J Immunol. 2000 Jun 15;164(12):6147-57. PMID: 10843664.
Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity.
Meng L, et al. Proc Natl Acad Sci U S A. 1999 Aug 31;96(18):10403-8. PMID: 10468620.
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