oprozomib 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

Gastrointestinal toxicities are commonly reported following treatment with proteasome inhibitors. The first-generation proteasome inhibitor, bortezomib, induces significant gastrointestinal side effects including nausea, vomiting, diarrhoea, and constipation, occurring in up to 84% of patients. Despite the development of safer proteasome inhibitors, such as carfilzomib, gastrointestinal toxicities remain some of the most common side effects. This review aims to summarize the previous literature on proteasome inhibitor-induced gastrointestinal toxicities, report on recent updates in the field, and investigate possible mechanisms of this toxicity.. Updates in the literature have included a direct comparison of the safety of approved proteasome inhibitors, bortezomib and carfilzomib, reporting less neurotoxicity and similar gastrointestinal toxicity, from carfilzomib when compared with bortezomib. Many recent studies have investigated the safety of orally bioavailable proteasome inhibitors, such as ixazomib and oprozomib. However, little progress has been made in understanding the possible mechanisms of proteasome inhibitor-induced gastrointestinal toxicities.. Although recent studies have continued to report gastrointestinal toxicities resulting from proteasome inhibitor treatment, particularly when combined with other agents or when administered orally, the mechanisms of proteasome inhibitor-induced gut toxicity remain largely unexplored. Further studies are needed to investigate the pathophysiology of this toxicity to improve the safety of existing and novel proteasome inhibitors.

Topics: Antineoplastic Agents; Boron Compounds; Bortezomib; Clinical Trials as Topic; Gastrointestinal Diseases; Glycine; Humans; Oligopeptides; Proteasome Inhibitors

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

The proteasome inhibitors bortezomib, carfilzomib, and ixazomib, which are used in the treatment of multiple myeloma have greatly improved response rates. Several other proteasome inhibitors, including delanzomib and oprozomib, are in clinical trials. Carfilzomib and oprozomib are epoxyketones that form an irreversible bond with the 20S proteasome, whereas bortezomib, ixazomib, and delanzomib are boronic acids that form slowly reversible adducts. Several of the proteasome inhibitors have been shown to exhibit specific cardiac toxicities. A primary neonatal rat myocyte model was used to study the relative myocyte-damaging effects of five proteasome inhibitors with a view to identifying potential class differences and the effect of inhibitor binding kinetics. Bortezomib was shown to induce the most myocyte damage followed by delanzomib, ixazomib, oprozomib, and carfilzomib. The sensitivity of myocytes to proteasome inhibitors, which contain high levels of chymotrypsin-like proteasomal activity, may be due to inhibition of proteasomal-dependent ongoing sarcomeric protein turnover. All inhibitors inhibited the chymotrypsin-like proteasomal activity of myocyte lysate in the low nanomolar concentration range and exhibited time-dependent inhibition kinetics characteristic of slow-binding inhibitors. Progress curve analysis of the inhibitor concentration dependence of the slow-binding kinetics was used to measure second-order "on" rate constants for binding. The second-order rate constants varied by 90-fold, with ixazomib reacting the fastest, and oprozomib the slowest. As a group, the boronic acid drugs were more damaging to myocytes than the epoxyketone drugs. Overall, inhibitor-induced myocyte damage was positively, but not significantly, correlated with their second-order rate constants.

Topics: Animals; Animals, Newborn; Boron Compounds; Boronic Acids; Bortezomib; Cardiotoxicity; Cell Survival; Dose-Response Relationship, Drug; Epoxy Compounds; Glycine; Humans; K562 Cells; Ketones; Kinetics; Myocytes, Cardiac; Oligopeptides; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Protein Binding; Rats, Sprague-Dawley; Threonine

Osteosarcoma, a common malignancy in large dog breeds, typically metastasises from long bones to lungs and is usually fatal within 1 to 2 years of diagnosis. Better therapies are needed for canine patients and their human counterparts, a third of whom die within 5 years of diagnosis. We compared the in vitro sensitivity of canine osteosarcoma cells derived from 4 tumours to the currently used chemotherapy drugs doxorubicin and carboplatin, and 4 new anti-cancer drugs. Agents targeting histone deacetylases or PARP were ineffective. Two of the 4 cell lines were somewhat sensitive to the BH3-mimetic navitoclax. The proteasome inhibitor bortezomib potently induced caspase-dependent apoptosis, at concentrations substantially lower than levels detected in the bones and lungs of treated rodents. Co-treatment with bortezomib and either doxorubicin or carboplatin was more toxic to canine osteosarcoma cells than each agent alone. Newer proteasome inhibitors carfilzomib, ixazomib, oprozomib and delanzomib manifested similar activities to bortezomib. Human osteosarcoma cells were as sensitive to bortezomib as the canine cells, but slightly less sensitive to the newer drugs. Human osteoblasts were less sensitive to proteasome inhibition than osteosarcoma cells, but physiologically relevant concentrations were toxic. Such toxicity, if replicated in vivo, may impair bone growth and strength in adolescent human osteosarcoma patients, but may be tolerated by canine patients, which are usually diagnosed later in life. Proteasome inhibitors such as bortezomib may be useful for treating canine osteosarcoma, and ultimately may improve outcomes for human patients if their osteoblasts survive exposure in vivo, or if osteoblast toxicity can be managed.

Topics: Aniline Compounds; Animals; Antineoplastic Agents; Bone Neoplasms; Boron Compounds; Boronic Acids; Bortezomib; Carboplatin; Cell Line, Tumor; Dog Diseases; Dogs; Doxorubicin; Glycine; Humans; Oligopeptides; Osteosarcoma; Proteasome Inhibitors; Sulfonamides; Threonine

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: Antineoplastic Agents; Boron Compounds; Boronic Acids; Bortezomib; Clinical Trials as Topic; Drug Resistance, Neoplasm; Glycine; Humans; Immunologic Factors; Lenalidomide; Multiple Myeloma; Oligopeptides; Protease Inhibitors; Pyrazines; Survival Rate; Thalidomide; Threonine