Marizomib, A Potent Second Generation Proteasome Inhibitor from Natural Origin

Ma, Long; Diao, Aipo

doi:10.2174/1871520614666141114202606

Cited by 33 publications

(18 citation statements)

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“…Marizomib recently received orphan drug status for the treatment of multiple myeloma and is currently undergoing clinical evaluation (Ma and Diao, 2014).…”

Section: Targeting the Ups In Cancermentioning

confidence: 99%

Inhibition of proteasome deubiquitinase activity: a strategy to overcome resistance to conventional proteasome inhibitors?

Selvaraju

Mazurkiewicz

Wang

et al. 2015

Drug Resistance Updates

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The ubiquitin-proteasome system (UPS) is the primary mechanism controlling the degradation of damaged, unwanted or short-lived proteins in eukaryotic cells. In addition to protein homeostasis, the UPS has also emerged as a critical node in the regulation of signalling pathways implicated in the growth and survival of cancer cells. The absolute dependency of cancer cells on a functioning UPS has been exploited in the development of anti-cancer therapies as exemplified by development of proteasome inhibitors for the treatment of certain leukemic malignancies.Deubiquitinases (DUBs) are enzyme components of the UPS that catalyse re-editing of poly ubiquitin chains and/or removal of ubiquitin en bloc from target substrates leading to alterations in protein stability and/or downstream signalling. There is a growing recognition that targeting DUB activity may be a feasible option for the development of novel anti-cancer therapies. In particular inhibition of proteasomal cysteine DUBs (i.e. USP14 and UCHL5) has been shown to be particularly cytotoxic to cancer cells leading to the accumulation of ubiquitinated proteins and proteotoxic stress. In this review we focus on the mechanisms of action of proteasome DUB inhibitors as well as the potential of such compounds to circumvent acquired drug resistance in cancer patients.

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“…Marizomib recently received orphan drug status for the treatment of multiple myeloma and is currently undergoing clinical evaluation (Ma and Diao, 2014).…”

Section: Targeting the Ups In Cancermentioning

confidence: 99%

Inhibition of proteasome deubiquitinase activity: a strategy to overcome resistance to conventional proteasome inhibitors?

Selvaraju

Mazurkiewicz

Wang

et al. 2015

Drug Resistance Updates

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show abstract

“…9 Chemoprevention was regarded as one of the best ways for inhibiting, reversing or delaying carcinogenesis by using natural, dietary or synthetic agents. 10 In our previous research, Rhizoma paridis saponins (RPS) as a potent antitumor agent elicited programmed cell death and inhibited metastases in murine pulmonary adenocarcinoma of Lewis mice. 11 It also inhibited urethane-induced lung carcinogenesis in mice through reducing oxidative stress injury, inflammatory action, proliferative factor and activation of apoptosis.…”

mentioning

confidence: 99%

Inhibition of lung cancer in diethylnitrosamine‐induced mice by Rhizoma paridis saponins

Man

Qiu

et al. 2017

Molecular Carcinogenesis

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Lung cancer is the foremost cause of cancer mortality and a growing economic burden worldwide. Rhizoma paridis saponins (RPS) have been reported to exhibit potential anti-tumor effects on many kinds of tumor models. The present study was designed to investigate the mechanism-based chemopreventive nature of RPS against DEN-induced lung carcinogenesis in Kunming mice. As a result, the treatment with RPS reduced the severity of pulmonary histopathology. The mechanism of its antitumor effect involved in (a) reducing oxidative stress injury through up-regulating activities of CAT and SOD; (b) down-regulating the levels of inflammatory factors, like TNF-α, IL6, COX-2, and PGE2; (c) activation of caspase-3 and up-regulating the pro-apoptotic protein Bax; (d) decreasing the expression of PCNA; (e) depressing the expression of cancer stem cells marker CD133; (f) suppressing aberrant expression of cytokeratin 8 and 18; and (g) inhibiting EGFR/ PI3 K/Akt, EGFR/Ras/Erk and NF-κB pathways. Taken together, RPS would be a potent agent inhibiting lung tumor in the future.

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“…A third promising class of proteasome inhibitors under development possess a β-lactone which covalently modifies Thr1O to generate an acyl-enzyme adduct. [11] An example is salinosporamide A (Marizomib, 3 ), which is a β-lactone containing proteasome inhibitor designated as an orphan drug for multiple myeloma [12] and is in Phase I/II clinical studies for the treatment of multiple myeloma, leukemia, and solid tumors (Figure 1). [13] Despite these advances, drug resistance to proteasome inhibitors through active site mutations and upregulation of ChT-L subunits, continues to necessitate the development of novel inhibitors for cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

A strategy for dual inhibition of the proteasome and fatty acid synthase with belactosin C-orlistat hybrids

Zhu

Harshbarger

Robles

et al. 2017

Bioorganic & Medicinal Chemistry

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The proteasome, a validated cellular target for cancer, is central for maintaining cellular homeostasis, while fatty acid synthase (FAS), a novel target for numerous cancers, is responsible for palmitic acid biosynthesis. Perturbation of either enzymatic machine results in decreased proliferation and ultimately cellular apoptosis. Based on structural similarities, we hypothesized that hybrid molecules of belactosin C, a known proteasome inhibitor, and orlistat, a known inhibitor of the thioesterase domain of FAS, could inhibit both enzymes. Herein, we describe proof-of-principle studies leading to the design, synthesis and enzymatic activity of several novel, β-lactone-based, dual inhibitors of these two enzymes. Validation of dual enzyme targeting through activity-based proteome profiling with an alkyne probe modeled after the most potent inhibitor, and preliminary serum stability studies of selected derivatives are also described. These results provide proof of concept for dual targeting of the proteasome and FAS-TE enabling a new approach for the development of drug-candidates with potential to overcome resistance.

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Marizomib, A Potent Second Generation Proteasome Inhibitor from Natural Origin

Cited by 33 publications

References 0 publications

Inhibition of proteasome deubiquitinase activity: a strategy to overcome resistance to conventional proteasome inhibitors?

Inhibition of proteasome deubiquitinase activity: a strategy to overcome resistance to conventional proteasome inhibitors?

Inhibition of lung cancer in diethylnitrosamine‐induced mice by Rhizoma paridis saponins

A strategy for dual inhibition of the proteasome and fatty acid synthase with belactosin C-orlistat hybrids

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