Targeting LMP-7 in Multiple Myeloma: The Therapeutic Potential of PR-924 Inhibitor

The introduction highlights the FDA's approval of bortezomib, a proteasome inhibitor for treating multiple myeloma (MM), but acknowledges the challenges of dose-limiting toxicities and drug resistance. It mentions the role of the 26S proteasome's catalytic subunits and their immunoproteasome counterparts, which are implicated in immune function and cytokine production. The immunoproteasome's role in MM cells is under investigation, with a focus on developing inhibitors to better target the ubiquitin-proteasome system (UPS) and reduce toxic side effects.

The study presents PR-924, an inhibitor that selectively targets the LMP-7 component of the proteasome, related to carfilzomib. It contains a ketopoxide moiety that modifies the proteasome's active sites. The research evaluated PR-924's impact on MM cell lines and primary patient cells in vitro and assessed its in vivo efficacy using two models of human MM in SCID mice: a subcutaneous tumor model and a model reflecting the MM-BM microenvironment.

The methods involved using various human MM cell lines and patient-derived tumor cells, with cell viability and apoptosis assessed through various assays. For in vivo studies, mice were inoculated with MM cells and treated with PR-924 or a control. The SCID-hu model involved injecting cells into human bone chips implanted in mice, with MM cell growth measured by human interleukin-6 receptor levels in serum.

Results showed that PR-924 significantly reduced MM cell growth and viability, inducing apoptosis. In vivo, it led to substantial tumor growth inhibition and decreased interleukin-6 receptor levels. PR-924 was well-tolerated and significantly extended survival in treated mice.

The conclusion asserts that PR-924's preclinical success identifies LMP-7 as a potential therapeutic target for MM treatment.