Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The proteasome is a multisubunit enzyme complex that plays a central role in the regulation of proteins that control cell-cycle progression and apoptosis, and has therefore become an important target for anticancer therapy. Before a protein is degraded, it is first flagged for destruction by the ubiquitin conjugation system, which ultimately results in the attachment of a polyubiquitin chain on the target protein. The proteasome's 19S regulatory cap binds the polyubiquitin chain, denatures the protein, and feeds the protein into the proteasome's proteolytic core. The proteolytic core is composed of 2 inner beta rings and 2 outer alpha rings. The 2 beta rings each contain 3 proteolytic sites named for their trypsin-like, post-glutamyl peptide hydrolase-like (PGPH) (i.e., caspase-like), or chymotrypsin-like activity. Inhibition of the proteasome results in cell-cycle arrest and apoptosis. In in vitro and in vivo animal studies, inhibition of the proteasome via bortezomib (VELCADE; formerly, PS-341, LDP-341, and MLN341) had antitumor activity against numerous tumor types either alone or in combination with conventional chemotherapeutic agents; these results provided the rationale for a broad clinical trial program. Bortezomib is currently in phase III trials for myeloma and is in early clinical development for numerous other tumor types.
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PMID:The proteasome: structure, function, and role in the cell. 1273 38

Histone deacetylase (HDAC) inhibitors are emerging as a promising new treatment strategy in hematologic malignancies. Here we show that NVP-LAQ824, a novel hydroxamic acid derivative, induces apoptosis at physiologically achievable concentrations (median inhibitory concentration [IC50] of 100 nM at 24 hours) in multiple myeloma (MM) cell lines resistant to conventional therapies. MM.1S myeloma cell proliferation was also inhibited when cocultured with bone marrow stromal cells, demonstrating ability to overcome the stimulatory effects of the bone marrow microenvironment. Importantly, NVP-LAQ824 also inhibited patient MM cell growth in a dose- and time-dependent manner. NVP-LAQ824-induced apoptotic signaling includes up-regulation of p21, caspase cascade activation, and poly (adenosine diphosphate [ADP]) ribose (PARP) cleavage. Apoptosis was confirmed with cell cycle analysis and annexin-propidium iodide staining. Interestingly, treatment of MM cells with NVPLAQ824 also led to proteasome inhibition, as determined by reduced proteasome chymotrypsin-like activity and increased levels of cellular polyubiquitin conjugates. Finally, a study using NVP-LAQ824 in a preclinical murine myeloma model provides in vivo relevance to our in vitro studies. Taken together, these findings provide the framework for NVP-LAQ824 as a novel therapeutic in MM.
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PMID:NVP-LAQ824 is a potent novel histone deacetylase inhibitor with significant activity against multiple myeloma. 1281 65

The 26S proteasome is an adenosine triphosphate-dependent multicatalytic protease that is responsible for most nonlysosomal intracellular protein degradation. To be selected for proteasomal degradation, proteins must be previously tagged with a polyubiquitin chain, which is then recognized by the proteasome; the ubiquitin chain is removed by isopeptidases and the protein is hydrolysed to small polypeptides. In addition to removing damaged/unnecessary proteins, the proteasome is also an important mechanism of regulation of some key regulatory proteins and their inhibitors. This regulation is crucial for the control of many cellular processes, including activation of transcription factors, cell cycle progression, and apoptosis. The critical role of the ubiquitin-proteasome pathway in tumor cells has led to the investigation of proteasome inhibition as a potential anticancer therapy. The dipeptide boronic acid analogue bortezomib, formerly known as PS-341, is a potent, highly selective, and reversible proteasome inhibitor. The first drug of this class to be used in the clinical setting, it has recently been approved by the US Food and Drug Administration for the treatment of relapsed and refractory multiple myeloma and is currently being tested in clinical trials for the treatment of a wide variety of malignancies. This article provides a summary of the biology of the ubiquitin-proteasome pathway, reviews the available preclinical and clinical data of proteasome inhibition as a therapeutic strategy in breast cancer, and discusses future combination regimens involving bortezomib.
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PMID:Targeting the ubiquitin-proteasome pathway in breast cancer. 1524 20

The highly conserved eukaryotic ubiquitin-proteasome system (UP-S) plays a pivotal role in protein homeostasis and is critical in regulating normal and cancer-related cellular processes. The hierarchical nature of the UP-S provides a rich source of molecular targets for specific intervention and has therefore arisen as a promising approach to innovative anticancer therapies. The first in class proteasome inhibitory agent Bortezomib (Velcade) has recently obtained regulatory approval for the treatment of multiple myeloma. Ubiquitin-mediated degradation is a complex process that is comprised of well defined steps involving ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s) and ubiquitin ligases (E3s). Although a single E1 activates the ubiquitin conjugation machinery, a large number of E2 conjugating enzymes and E3 ligases are now known to exist. Proteins tagged with ubiquitin are subsequently recognised by the proteasome for digestion and fragmentation. The enzymatic nature, multitude of E3s and their specific substrate recognition predestines them as therapeutic targets. This article will review known inhibitors of the proteasome and their molecular mechanisms as well as ongoing developments and promising avenues for targeting substrate-specific E3 ligases that are likely to yield a new class of therapeutics that will serve and complement the armamentarium of anticancer drugs.
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PMID:The ubiquitin-mediated protein degradation pathway in cancer: therapeutic implications. 1545 46

The ubiquitin-proteasome proteolytic pathway plays a major role in selective protein degradation and regulates various cellular events including cell cycle progression, transcription, DNA repair, signal transduction, and immune response. Ubiquitin, a highly conserved small protein in eukaryotes, attaches to a target protein prior to degradation. The polyubiquitin chain tagged to the target protein is recognized by the 26S proteasome, a high-molecular-mass protease subunit complex, and the protein portion is degraded by the 26S proteasome. The potential of specific proteasome inhibitors, which act as anti-cancer agents, is now under intensive investigation, and bortezomib (PS-341), a proteasome inhibitor, has been recently approved by FDA for multiple myeloma treatment. Since ubiquitination of proteins requires the sequential action of three enzymes, ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin-protein ligase (E3), and polyubiquitination is a prerequisite for proteasome-mediated protein degradation, inhibitors of E1, E2, and E3 are reasonably thought to be drug candidates for treatment of diseases related to ubiquitination. Recently, various compounds inhibiting the ubiquitin-proteasome pathway have been isolated from natural resources. We also succeeded in isolating inhibitors against the proteasome and E1 enzyme from marine natural resources. In this review, we summarize the structures and biological activities of natural products that inhibit the ubiquitin-proteasome proteolytic pathway.
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PMID:Natural products inhibiting the ubiquitin-proteasome proteolytic pathway, a target for drug development. 1661 Oct 64

Deregulation of the ubiquitin-proteasome system has been implicated in the pathogenesis of many human diseases, including cancer, neurodegenerative disorders and viral diseases. The recent approval of the proteasome inhibitor bortezomib (Velcade) for the treatment of multiple myeloma and mantle cell lymphoma establishes this system as a valid target for cancer treatment. A promising alternative to targeting the proteasome itself would be to interact at the level of the upstream, ubiquitin conjugation/deconjugation system to generate more specific, less toxic anticancer agents. Ubiquitin specific proteases (USP) are de-ubiquitinating enzymes which remove ubiquitin from specific protein substrates and allow protein salvage from proteasome degradation, regulation of protein localization or activation. Due to their protease activity and their involvement in several pathologies, USPs are emerging as potential target sites for pharmacological interference in the ubiquitin regulatory machinery. We will review here this class of enzymes from target validation to small molecule drug discovery.
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PMID:Targeting ubiquitin specific proteases for drug discovery. 1796 5

Recently, the ubiquitin proteasome system (UPS) has matured as a drug discovery arena, largely on the strength of the proven clinical activity of the proteasome inhibitor Velcade in multiple myeloma. Ubiquitin ligases tag cellular proteins, such as oncogenes and tumor suppressors, with ubiquitin. Once tagged, these proteins are degraded by the proteasome. The specificity of this degradation system for particular substrates lies with the E3 component of the ubiquitin ligase system (ubiquitin is transferred from an E1 enzyme to an E2 enzyme and finally, thanks to an E3 enzyme, directly to a specific substrate). The clinical effectiveness of Velcade (as it theoretically should inhibit the output of all ubiquitin ligases active in the cell simultaneously) suggests that modulating specific ubiquitin ligases could result in an even better therapeutic ratio. At present, the only ubiquitin ligase leads that have been reported inhibit the degradation of p53 by Mdm2, but these have not yet been developed into clinical therapeutics. In this review, we discuss the biological rationale, assays, genomics, proteomics and three-dimensional structures pertaining to key targets within the UPS (SCFSkp2 and APC/C) in order to assess their drug development potential. Publication history: Republished from Current BioData's Targeted Proteins database (TPdb; http://www.targetedproteinsdb.com).
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PMID:Wrenches in the works: drug discovery targeting the SCF ubiquitin ligase and APC/C complexes. 1804 46

The Ubiquitin-proteasome pathway (UPP) regulates normal intracellular protein degradation processes essential for cell cycle progression, inflammation, transcription, DNA replication, and apoptosis. Blockade of UPP using proteasome inhibitor Bortezomib (Velcade) is an effective therapy for relapsed/refractory multiple myeloma (MM). Both oligonucleotide microarrays and proteomic studies are delineating the molecular mechanisms mediating Bortezomib-induced cytotoxicity, defining targets of sensitivity vs resistance, allowing for the development of next generation therapies, and providing the rationale for combination therapies.
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PMID:Targeting proteasomes as therapy in multiple myeloma. 1843 98

The Ubiquitin Drug Discovery & Diagnostics conference, held in Philadelphia, included topics covering new therapeutic developments in the field of ubiquitin drug research. This conference report highlights selected presentations on emerging ubiquitin targets in oncology and on proteasome inhibitor therapy for the treatment of multiple myeloma. Investigational drugs discussed include MLN-4924 and MLN-9708 (both Millennium Pharmaceuticals Inc), P-005091 (Progenra Inc), CEP-18770 (Cephalon Inc) and carfilzomib (Proteolix Inc).
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PMID:Ubiquitin Drug Discovery & Diagnostics 2009 - First Annual Conference. 1994 15

MCL1 is essential for the survival of stem and progenitor cells of multiple lineages, and is unique among pro-survival BCL2 family members in that it is rapidly turned over through the action of ubiquitin ligases. B- and mantle-cell lymphomas, chronic myeloid leukaemia, and multiple myeloma, however, express abnormally high levels of MCL1, contributing to chemoresistance and disease relapse. The mechanism of MCL1 overexpression in cancer is not well understood. Here we show that the deubiquitinase USP9X stabilizes MCL1 and thereby promotes cell survival. USP9X binds MCL1 and removes the Lys 48-linked polyubiquitin chains that normally mark MCL1 for proteasomal degradation. Increased USP9X expression correlates with increased MCL1 protein in human follicular lymphomas and diffuse large B-cell lymphomas. Moreover, patients with multiple myeloma overexpressing USP9X have a poor prognosis. Knockdown of USP9X increases MCL1 polyubiquitination, which enhances MCL1 turnover and cell killing by the BH3 mimetic ABT-737. These results identify USP9X as a prognostic and therapeutic target, and they show that deubiquitinases may stabilize labile oncoproteins in human malignancies.
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PMID:Deubiquitinase USP9X stabilizes MCL1 and promotes tumour cell survival. 2002 29


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