From Bortezomib to other Inhibitors of the Proteasome and Beyond

Abstract

The cancer drug discovery field has placed much emphasis on the identification of novel and cancer-specific molecular targets. A rich source of such targets for the design of novel anti-tumor agents is the ubiqutin-proteasome system (UP-S), a tightly regulated, highly specific pathway responsible for the vast majority of protein turnover within the cell. Because of its critical role in almost all cell processes that ensure normal cellular function, its inhibition at one point in time was deemed non-specific and therefore not worth further investigation as a molecular drug target. However, today the proteasome is one of the most promising anti-cancer drug targets of the century. The discovery that tumor cells are in fact more sensitive to proteasome inhibitors than normal cells indeed paved the way for the design of its inhibitors. Such efforts have led to bortezomib, the first FDA approved proteasome inhibitor now used as a frontline treatment for newly diagnosed multiple myeloma (MM), relapsed/refractory MM and mantle cell lymphoma. Though successful in improving clinical outcomes for patients with hematological malignancies, relapse often occurs in those who initially responded to bortezomib. Therefore, the acquisition of bortezomib resistance is a major issue with its therapy. Furthermore, some neuro-toxicities have been associated with bortezomib treatment and its efficacy in solid tumors is lacking. These observations have encouraged researchers to pursue the next generation of proteasome inhibitors, which would ideally overcome bortezomib resistance, have reduced toxicities and a broader range of anti-cancer activity. This review summarizes the success and limitations of bortezomib, and describes recent advances in the field, including, and most notably, the most recent FDA approval of carfilzomib in July, 2012, a second generation proteasome inhibitor. Other proteasome inhibitors currently in clinical trials and those that are currently experimental grade will also be discussed.

Endoplasmic reticulum–retained podocin mutants are massively degraded by the proteasome

“…Interestingly, Bz has been reported to rescue other misfolded mutant proteins back to the PM in vitro and in vivo (41,42). Additionally, second generation proteasomal inhibitors are currently being tested in clinical trials with less severe side effects than those of Bz, such as neurotoxicity or lymphopenia (43). Altogether, although we lack in vivo studies, we propose that increasing ng-Pod R138Q protein levels through the inhibition of the proteasomal degradation may be a reasonable strategy to treat patients with p.R138Q mutation and possibly with other ER retained podocin mutations.…”

VR23: A Quinoline–Sulfonyl Hybrid Proteasome Inhibitor That Selectively Kills Cancer via Cyclin E–Mediated Centrosome Amplification

“…Since the first proteasome inhibitor bortezomib (Velcade) was approved by the FDA for the treatment of multiple myeloma in 2003, many proteasome inhibitors have been reported (18,19). Although bortezomib and carfilzomib (Kyprolis) are quite effective for the treatment of multiple myeloma and other blood cancers, they either show considerable side effects or are ineffective against solid tumors (20)(21)(22).…”

Modulation of NF-κB Signaling as a Therapeutic Target in Autoimmunity

“…130,131 Bortezomib forms covalent adducts with active site threonines on the proteasome, while coinhibiting the chymotrypsin-like and caspase-like active sites, resulting in the disruption of the proteasome's proteolytic function. This synthetic inhibitor is currently used clinically in the treatment of several malignancies, including multiple myeloma (MM), [132][133][134][135] and in the treatment of antibody-mediated allograft rejection in posttransplant patients. 136,137 Bortezomib's major mechanism of action has been identified as the selective destruction of antibody-producing plasma cells, and as such, it may also be efficacious in the treatment of antibody-mediated autoimmune diseases.…”