Title:From Bortezomib to other Inhibitors of the Proteasome and Beyond
Volume: 19
Issue: 22
Author(s): Daniela Buac, Min Shen, Sara Schmitt, Fathima Rani Kona, Rahul Deshmukh, Zhen Zhang, Christine Neslund-Dudas, Bharati Mitra and Q. Ping Dou
Affiliation:
Keywords:
Ubiquitin-proteasome system (UP-S), inhibitors of the 20S proteasome, bortezomib, drug discovery, cancer, natural compounds,
clinical studies.
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.
