oprozomib and marizomib

The proteasome is the central component of the main cellular protein degradation pathway. During the past four decades, the critical function of the proteasome in numerous physiological processes has been revealed, and proteasome activity has been linked to various human diseases. The proteasome prevents the accumulation of misfolded proteins, controls the cell cycle, and regulates the immune response, to name a few important roles for this macromolecular "machine." As a therapeutic target, proteasome inhibitors have been approved for the treatment of multiple myeloma and mantle cell lymphoma. However, inability to sufficiently inhibit proteasome activity at tolerated doses has hampered efforts to expand the scope of proteasome inhibitor-based therapies. With emerging new modalities in myeloma, it might seem challenging to develop additional proteasome-based therapies. However, the constant development of new applications for proteasome inhibitors and deeper insights into the intricacies of protein homeostasis suggest that proteasome inhibitors might have novel therapeutic applications. Herein, we summarize the latest advances in proteasome inhibitor development and discuss the future of proteasome inhibitors and other proteasome-based therapies in combating human diseases.

Topics: Antineoplastic Agents; Boron Compounds; Bortezomib; Glycine; Humans; Lactones; Molecular Targeted Therapy; Multiple Myeloma; Oligopeptides; Proteasome Inhibitors; Proteostasis; Pyrroles

Bortezomib was the first proteasome inhibitor (PI) discovered and demonstrated great efficacy in myeloma, both in vitro and in patients. However, still many patients ultimately relapse and there is the need for novel therapies. A second generation of PI have been discovered, potentially more effective ands some also orally administered. Carfilzomib is an irreversible proteasome inhibitor that showed great efficacy in clinical studies. Ixazomib is an oral compound that has been introduced recently in the therapeutic spectrum. Novel agents such as Marizomib seem promising in the fact that can also pass through the blood brain barrier and maybe effective also in CNS muyeloma. This review focus on all proteasome inhibitors available in clinics and the new ones coming soon.

Topics: Animals; Boronic Acids; Bortezomib; Central Nervous System Neoplasms; Drug Discovery; Humans; Lactones; Multiple Myeloma; Neoplasm Recurrence, Local; Oligopeptides; Proteasome Inhibitors; Pyrroles; Threonine

The ubiquitin-proteasome pathway (UPP), which influences essential cellular functions including cell growth, differentiation, apoptosis, signal transduction, antigen processing and inflammatory responses, has been considered as one of the most important cellular protein degradation approaches. Proteasome functions as a gatekeeper, which controls the execution of protein degradation and plays a critical role in the ubiquitin-proteasome pathway. The unfolding of the close connection between proteasome and cancer provides a potential strategy for cancer treatment by using proteasome inhibitors. Small molecular inhibitors of varied structures and potency against proteasome have been discovered in recent years, with bortezomib and carfilzomib having been successfully approved for clinical application while some other promising candidates are currently under clinical trials. Herein, we review the development history of drugs and candidates that target the 20S proteasome, structure-activity relationships (SARs) of various proteasome inhibitors, and related completed or ongoing clinical trials.

Topics: Boron Compounds; Boronic Acids; Bortezomib; Glycine; Humans; Lactones; Neoplasms; Oligopeptides; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Pyrazines; Pyrroles; Structure-Activity Relationship; Threonine

The proteasome is an intracellular enzyme complex that degrades ubiquitin-tagged proteins and thereby regulates protein levels within the cell. Given this important role in maintaining cellular homeostasis, it is perhaps somewhat surprising that proteasome inhibitors have a therapeutic window. Proteasome inhibitors have demonstrated clinical efficacy in the treatment of multiple myeloma and mantle cell lymphoma and are under evaluation for the treatment of other malignancies. Bortezomib is the first and only Food and Drug Administration-approved proteasome inhibitor that inhibits this enzyme complex in a reversible fashion. Although bortezomib improves clinical outcomes when used as a single agent, most patients do not respond to this drug and those who do respond almost uniformly relapse. As such, efforts are underway to develop proteasome inhibitors that act through mechanisms distinct from that of bortezomib. Specifically, inhibitors that bind the active site of the proteasome and inhibit the complex irreversibly have been developed and are in advanced clinical trials. Inhibitors that act on sites of the proteasome outside of the catalytic center have also been identified and are in preclinical development. In this review, we discuss the structure and function of the proteasome. We then focus on the molecular biology, chemistry, and the preclinical and clinical efficacy of novel proteasome inhibitors as strategies to inhibit this target and overcome some forms of bortezomib resistance.

Topics: Allosteric Site; Animals; Antineoplastic Agents; Apoptosis; Boronic Acids; Bortezomib; Cell Line, Tumor; Chloroquine; Clioquinol; Drug Resistance, Neoplasm; Humans; Hydroxyquinolines; Lactones; Neoplasms; Oligopeptides; Protease Inhibitors; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Pyrazines; Pyrroles; Threonine; Ubiquitinated Proteins; Ubiquitination

We sought to evaluate the activity and safety of these novel proteasome inhibitors (PIs) (carfilzomib, ixazomib, oprozomib and marizomib) containing regimens (single, doublet and triplet) for relapsed/refractory multiple myeloma (R/RMM).. We searched published reports including these novel PIs containing regimens for R/RMM.. Finally, we identified 28 prospective studies that evaluated 4123 patients. Pooled analysis showed that novel PIs doublet combinations attained an impressive overall response rate (ORR) of 67%, which was higher than that of 22% from novel PIs single-agent (p < .001). And, the same trends favoring novel PIs doublet combinations were also shown in at least very good partial response (≥VGPR) and clinical benefit rate (CBR) analysis. Meanwhile, the ORR of 70% from novel PIs triplet regimens seemed to be similar to that of 67% from novel PIs doublet combinations (p = .54). And, there were no difference between them in ≥VGPR and CBR analysis. Compared to standard therapy, novel PIs combinations clearly benefited patients with R/RMM in terms of overall survival (HR, 0.79; p= .01), progression free survival(HR, 0.64; p = .01), overall response rate (RR = 1.21 p < .001).. Novel PIs doublet combinations attained superior response outcomes over novel PIs single-agent in patients with R/RMM. Meanwhile, novel PIs triplet combinations had similar response outcomes with novel PIs doublet combinations. Compared to standard therapy, novel PIs combinations clearly prolonged survival for patients with R/RMM.

Topics: Antineoplastic Combined Chemotherapy Protocols; Boron Compounds; Glycine; Humans; Lactones; Multiple Myeloma; Neoplasm Recurrence, Local; Oligopeptides; Proteasome Inhibitors; Pyrroles; Retrospective Studies

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Boron Compounds; Bortezomib; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Cyclic N-Oxides; Drug Approval; Drug Discovery; Glycine; Humans; Indolizines; Lactones; Lenalidomide; Multiple Myeloma; Oligopeptides; Practice Guidelines as Topic; Pyridinium Compounds; Pyrroles; Thalidomide