Characterization of novel proteasome inhibitors for treatment of Multiple Myeloma

In order to maintain homeostasis, cells consistently produce new proteins, and degrade unnecessary proteins. To that end, protein degradation pathways was evolved. In eukaryotic cells, the major protein degradation pathway is the ubiquitin-proteasome system.

Multiple Myeloma (MM) is a cancer of plasma cells, which are responsible for secreting antibodies. When the proteasome in MM cells is inhibited, the cells accumulate proteins (antibodies) that can`t degrade. The proteins accumulation induces apoptosis of the MM cells. Therefore, proteasome inhibitors can be used to treat MM.

A novel, copper-based proteasome inhibitor, called NS250, was developed in Prof. Navon`s lab at Weizmann Institute of Science. In order to improve the inhibitor efficiency, and develop a therapeutic inhibitor, a derivative of the inhibitor called NS625 was synthesized. NS625 features chemical modifications, which adjust the inhibitor to his active site`s chemical environment.

The goal of the research was to characterize the effect of NS250 and NS625 on different types of proteasomes, study the chemical mechanism of the inhibitors, and evaluate the therapeutic potential of the inhibitors.

The results have shown that both NS250 and NS625 specifically inhibit the proteasome of different organisms. Furthermore, it was found that the chemical modifications of NS625 indeed improve the effect of the inhibitor on the proteasome. However, the original inhibitor, NS250, has higher therapeutic potential.

In addition, it was confirmed that the chemical mechanism of the inhibitors involves disulfide bond between two proteasome subunits.

The study results pave the way for future development of proteasome inhibitor-based treatment for MM.