Proteasome inhibitors: structure and function

Abstract

Since 2003, the US Food and Drug Administration approval of bortezomib, a proteasome inhibitor, has changed the management of hematologic malignancies and dramatically improved outcomes for patients with multiple myeloma and mantle cell lymphoma. Since that time, two additional proteasome inhibitors (carfilzomib and ixazomib) have been approved, with other agents and combinations currently under investigation. Proteasomes degrade ubiquitinated proteins or substrates through the ubiquitin-proteasome pathway, a pathway that is utilized in multiple myeloma because of the high protein turnover with immunoglobulin production. Proteasome inhibitors exploit dependence on this pathway, halting protein degradation that ultimately results in apoptosis and cell death. Here we will discuss the structure of the proteasome and the mechanisms of action for proteasome inhibitors to further understand their role in hematologic malignancies.

Keywords: bortezomib; multiple myeloma; proteasome inhibitors; ubiquitin-proteasome pathway.

Figure 1. Chemical Structures of bortezomib, carfilzomib and ixazomib

The circles highlight the active moieties of the individual proteasome inhibitors

Figure 2. Proteasome Structure

The 20S catalytic core binds to the 19S regulatory complex to form the 26S proteasome structure. Proteins that are tagged with ubiquitin bind to the 19S complex and are degraded at the proteolytic β subunits. Bortezomib, carfilzomib and ixazomib all inhibit the β5 subunit thereby inhibiting the catalytic activity of the proteasome.

Figure 3. Mechanism of Proteasome Inhibitors

Proteasome inhibition acts through multiple mechanisms to induce cell death. Inhibition of NF-κB results in downregulation of multiple pro-neoplastic pathways. Activation of the JNK pathway leads to caspase activation and apoptosis. Additionally, interference with the degradation of pro-apoptotic proteins such as Bim, BIK, BID, or Bax and an increase in NOXA activation promotes apoptosis. The depletion of ubiquitin and ER stress with activation of the unfolded protein response can promote apoptosis as well.