Proteasome inhibitors

Proteasome inhibitors are chemical substances that inhibit the catalytic activity of the 20S proteasome or the 26S proteasome via the 19S regulator.

The proteasome (from proteins + Greek soma = body] is a multicatalytic protease complex (peptidases) with an unusual enzyme mechanism. It plays a central role in intracellular protein degradation and assumes a crucial function in the regulation of the cell cycle. Without this "garbage disposal", cells would perish from their protein waste. The proteasome is particularly active in tumor cells. These central functions of the proteasome make this protease complex an important target in tumor therapy.

Inhibition of this natural protein degradation leads to a dysbalance of protein synthesis and degradation. This inhibition of the proteasome has a toxic effect on cells. Among other things, it results in a deficiency of necessary amino acids in the cell. This is one of the mechanisms by which cells enter cell death. Proteasome inhibitors also block certain signaling pathways, such as the NF-κB signaling pathway. Therefore, certain anti-apoptotic factors can no longer be produced, and the cell is also directed into cell death by this pathway.

Proteasome inhibitors such as bortezomib damage the proteasome of lymphoma cells more than of normal cells of the hematopoietic system. They of show excellent effects in the treatment of multiple myeloma (a disease with lympho-proliferative dysfunction of the B-cell system). The therapeutic efficiency of these preparations can be enhanced by combination with glucocorticoids, cytostatics or IMiDs.

Proteasome inhibitors are molecules from the substance classes of peptide-boric acids, peptide-epoxyketones and gamma-lactam-beta-lactones. Active substances are:

• Bortezomib (Velcade®)
• Carfilzomib (Kyprolis®)
• Ixazomib (Ninlaro®)