Targeted inhibition of the immunoproteasome is a potent strategy against models of multiple myeloma that overcomes resistance to conventional drugs and nonspecific proteasome inhibitors

摘要

Proteasome inhibition is a validated strategy for therapy of multiple myeloma, but this disease remains challenging as relapses are common, and often associated with increasing chemoresistance. Moreover, nonspecific proteasome inhibitors such as bortezomib can induce peripheral neuropathy and other toxicities that may compromise the ability to deliver therapy at full doses, thereby decreasing efficacy. One novel approach may be to target the immunoproteasome, a protea-somal variant found predominantly in cells of hematopoietic origin that differsfrom the constitutive proteasome found in most other cell types. Using purified preparations of constitutive and immuno-proteasomes, we screened a rationally designed series of peptidyl-aldehydes and identified several with relative specificity for the immunoproteasome. The most potent immunoproteasome-specific inhibitor, IPSI-00, preferentially targeted the pi subunit of the immunoproteasome in vitro and in cellulo in a dose-dependent manner. This agent induced accumulation of ubiquitin-protein conjugates, pro-apoptotic proteins, and activated caspase-mediated apoptosis. IPSI-00 potently inhibited proliferation in myeloma patient samples and other hematologic malignancies. Importantly, IPSI-00 was able to overcome conventional and novel drug resistance, including resistance to bortezomib. These findings provide a rationale for the translation of IPSIs to the clinic, where they may provide antimy-eloma activity with greater specificity and less toxicity than current inhibitors.