marizomib and ixazomib

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

The immunoproteasome, a specialized form of proteasome, is mainly expressed in lymphocytes and monocytes of jawed vertebrates and responsible for the generation of antigenic peptides for cell-mediated immunity. Overexpression of immunoproteasome have been detected in a wide range of diseases including malignancies, autoimmune and inflammatory diseases. Following the successful approval of constitutive proteasome inhibitors bortezomib, carfilzomib and Ixazomib, and with the clarification of immunoproteasome crystal structure and functions, a variety of immunoproteasome inhibitors were discovered or rationally developed. Not only the inhibitory activities, the selectivities for immunoproteasome over constitutive proteasome are essential for the clinical potential of these analogues, which has been validated by the clinical evaluation of immunoproteasome-selective inhibitor KZR-616 for the treatment of systemic lupus erythematosus. In this review, structure, function as well as the current developments of various inhibitors against immunoproteasome are going to be summarized, which help to fully understand the target for drug discovery.

Topics: Animals; Antineoplastic Agents; Autoimmune Diseases; Boron Compounds; Bortezomib; Glycine; Hematologic Neoplasms; Humans; Oligopeptides; Proteasome Endopeptidase Complex; Proteasome Inhibitors

Multiple Myeloma (MM) management is rapidly evolving, with a spectrum of novel treatments that have changed our approach to the therapy. Proteasome inhibitors (PIs) have revolutionized the scenario of both relapsed/refractory and newly diagnosed patients. The efficacy of bortezomib, the first PI approved, followed by carfilzomib and, the oral ixazomib, have been tested in several trials as single agents or in combination.. In this review, the authors summarize mechanism of action, efficacy and safety of proteasome inhibitors in MM and focus on data derived from clinical trials, analyzing adverse events and their relative management.. The authors believe that, currently, the best course of action in the treatment of MM is to use PIs in combination with immunomodulatory drugs (IMiDs) and/or with monoclonal antibodies for all patients. However, based on the patient-specific characteristics, it is important to avoid inappropriate discontinuation by knowing the single side effects of every agent in order to balance their efficacy and safety.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Boron Compounds; Bortezomib; Glycine; Hematologic Diseases; Humans; Lactones; Multiple Myeloma; Neoplasm Recurrence, Local; Oligopeptides; Proteasome Inhibitors; Pyrroles

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

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

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Boron Compounds; Boronic Acids; Bortezomib; Glycine; Histone Deacetylases; Humans; Immunologic Factors; Lactones; Lenalidomide; Molecular Targeted Therapy; Multiple Myeloma; Oligopeptides; Proteasome Inhibitors; Pyrazines; Pyrroles; Thalidomide