marizomib and delanzomib

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

Proteasomes are multisubunit enzyme complexes. They contain three enzymatic active sites which are termed chymotrypsin-like, trypsin-like, and caspase-like. The elementary function of the proteasomes is degradation of damaged proteins. Proteasome inhibition leads to accumulation of damaged protein, which leads to caspase activation and cell death. This relationship is used in cancer therapy. Bortezomib is the first proteasome inhibitor approved by the US Food and Drug Administration for the treatment of relapsed/refractory multiple myeloma. Carfilzomib belongs to the second generation of drugs, which was approved by the US FDA in 2012. Currently in the study phase there are four new inhibitors: ixazomib (MLN9780/MLN2238), delanzomib (CEP-18770), oprozomib (ONX0912/PR-047) and marizomib (NPI-0052).

Topics: Antineoplastic Agents; Apoptosis; Boronic Acids; Bortezomib; Caspases; Dipeptides; Humans; Lactones; Multiple Myeloma; Neoplasms; Oligopeptides; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Proteolysis; Pyrroles; Thiazoles; 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

The combination of X-ray crystallography and kinetic studies of proteasome:ligand complexes has proven to be an important tool in inhibitor analysis of this crucial protein degradation machinery. Here, we describe in detail the purification protocols, proteolytic activity assays, crystallisation methods, and structure determination for the yeast 20S proteasome (CP) in complex with its inhibitors. The fusion of these advanced techniques offers the opportunity to further optimise drugs which are already tested in different clinical phase studies, as well as to design new promising proteasome lead structures which might be suitable for their application in medicine, plant protection, and antibiotics.

Topics: Antineoplastic Agents; Boronic Acids; Bortezomib; Crystallography, X-Ray; Drug Design; Enzyme Inhibitors; Lactones; Multiple Myeloma; Oligopeptides; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Pyrazines; Pyrroles; Saccharomyces cerevisiae; Threonine