Discovery of a Potent, Selective, and Orally Active Proteasome Inhibitor for the Treatment of Cancer

Dorsey, Bruce D.; Iqbal, Mohamed; Chatterjee, Sankar; Menta, Ernesto; Bernardini, Raffaella; Bernareggi, A.; Cassarà, Paolo; D’Arasmo, Germano; Ferretti, Edmondo; Munari, Sergio De; Oliva, Ambrogio; Pezzoni, Gabriella; Allievi, Cecilia; Strepponi, Ivan; Ruggeri, Bruce; Ator, Mark A.; Williams, Michael; Mallamo, John P.

doi:10.1021/jm7010589

Cited by 136 publications

(103 citation statements)

References 27 publications

(46 reference statements)

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“…As the essential role of the proteasome in cell function, inhibitors of this multicatalytic complex are potential drugs suitable in various therapeutic applications. Many natural and synthetic molecules have been studied as 20S catalytic subunits inhibitors [10][11][12][13][14][15][16][17][18][19] , among those the boronic pseudodipeptide bortezomib was the first FDA approved proteasome inhibitor for the treatment of multiple myeloma (MM) and recently carfilzomib became the second FDA-approved to treat MM in advanced state 20,21 .…”

Section: Introductionmentioning

confidence: 99%

Studies of C-terminal naphthoquinone dipeptides as 20S proteasome inhibitors

Scotti¹,

Trapella²,

Ferretti³

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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The ubiquitin proteasome pathway is crucial in regulating many processes in the cell. Modulation of proteasome activities has emerged as a powerful strategy for potential therapies against much important pathologies. In particular, specific inhibitors may represent a useful tool for the treatment of tumors. Here, we report studies of a new series of peptide-based analogues bearing a naphthoquinone pharmacophoric unit at the C-terminal position. Some derivatives showed inhibition in the mM range of the post-acidic-like and chymotrypsin-like active sites of the proteasome.

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Section: Introductionmentioning

confidence: 99%

Studies of C-terminal naphthoquinone dipeptides as 20S proteasome inhibitors

Scotti¹,

Trapella²,

Ferretti³

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…The proteasome inhibitors in clinical development have the greatest potency for the CT-L active site of the proteasome (24,27,36,38,39), but they differ in their activity against the other catalytic sites. The development of compounds with different selectivity profiles will help address the question of what combination of proteasome site inhibition provides maximal antitumor effects and the best therapeutic index.…”

Section: Next-generation Proteasome Inhibitors In Clinical Developmentmentioning

confidence: 99%

Molecular Pathways: Targeting Proteasomal Protein Degradation in Cancer

Molineaux

2012

Clinical Cancer Research

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With the approval by the U.S. Food and Drug Administration of bortezomib for the treatment of multiple myeloma and mantle cell lymphoma, the proteasome was clinically validated as a target in oncology. The proteasome is part of a complex cellular pathway that controls the specificity and rate of degradation of the majority of proteins in the cell. The search for additional drug targets in the proteasomal pathway is ongoing. In parallel, the next generation of proteasome inhibitors, exhibiting some properties distinct from that of bortezomib, are currently being studied in clinical trials. The key question will be whether these distinctions can improve upon the clinical efficacy and safety standards established by bortezomib and refine our understanding of the mechanism by which proteasome inhibitors are effective in the treatment of cancer.

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“…Proteasome inhibitors have also been identified from plant extracts. This is the case for celastrol from the Chinese medicinal orally-active inhibitor of the chymotrypsin-like activity [64,65]. These proteasome inhibitors are primarily designed as anticancer agents but they can be of interest for other pathologies characterized by alterations in the proteasome proteolytic pathway including autoimmune and inflammatory diseases, myocardial infarction, and ischemic brain injury [66].…”

Section: Natural Product-biological Target: a Pas De Deux In Drug Dismentioning

confidence: 99%

Ready for a comeback of natural products in oncology

Bailly

2009

Biochemical Pharmacology

100

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(186 words)Since the late 1990s and the rapid expansion of monoclonal antibodies and synthetic protein kinase inhibitors in oncology, anticancer natural products fell out of fashion with the pharmaceutical industry. But in 2007 with the approval of three new drugs derived from natural products, the emergence of promising antitumor compounds from microorganisms (e.g. alvespimycin, salinosporamide) and the growing importance of new formulations of known natural product-derived drugs (nanoparticle formulations, oral forms), we are witnessing a new wave for natural products in oncology. The recent approval of the microtubule-targeted epothilone derivative ixabepilone (Ixempra ® ), the DNA-alkylating marine alkaloid trabectedin (Yondelis ® ) and the inhibitor of mTOR protein kinase temsirolimus (Torisel ® ) is emblematic of the evolution of the field which combines the long established finding of conventional cytotoxic agents and the emergence of molecularly targeted therapeutics. These three examples also illustrate the increasing importance of microbial sources for the discovery of medically useful natural products. The contribution of innovative biological targets is also highlighted here, with references to proteasome inhibitors and novel approaches such as manipulation of mRNA splicing. Altogether, these observations plead for the return of natural products in oncology.

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Discovery of a Potent, Selective, and Orally Active Proteasome Inhibitor for the Treatment of Cancer

Cited by 136 publications

References 27 publications

Studies of C-terminal naphthoquinone dipeptides as 20S proteasome inhibitors

Studies of C-terminal naphthoquinone dipeptides as 20S proteasome inhibitors

Molecular Pathways: Targeting Proteasomal Protein Degradation in Cancer

Ready for a comeback of natural products in oncology

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