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 sub
cutaneous 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.
How to Use Synapse Database to Search and Analyze Translational Medicine Data?
The transational medicine section of the Synapse database supports searches based on fields such as drug, target, and indication, covering the T0-T3 stages of translation. Additionally, it offers a historical conference search function as well as filtering options, view modes, translation services, and highlights summaries, providing you with a unique search experience.

Taking obesity as an example, select "obesity" under the indication category and click search to enter the Translational Medicine results list page. By clicking on the title, you can directly navigate to the original page.

By clicking the analysis button, you can observe that GLP-1R treatment for obesity has gained significant attention over the past three years, with preclinical research still ongoing in 2023. Additionally, there are emerging potential targets, such as GDF15, among others.

Click on the image below to go directly to the Translational Medicine search interface.
