ONX 0914

In this study, we used ONX 0914, an LMP7/LMP2-selective inhibitor of the IP, to study the effect of IP inhibition on B cells and antibody production...Furthermore, IP inhibition neither impaired vaccine-induced antibody responses, nor affected different B cell populations in two different vaccination models. These findings suggest that IP inhibition does not compromise vaccination efficacy and anti-viral humoral immunity, supporting the potential of IP-targeted therapies for autoimmune diseases.

Proteasome inhibitors (PIs) bortezomib, carfilzomib and ixazomib are approved for the treatment of multiple myeloma and mantle cell lymphoma and have clinical activity in acute lymphoblastic leukemia (ALL). Treatment of KMT2A::AFF1 ALL cells with M3258, ONX-0914, and bortezomib induced proteotoxic stress that was prevented by the protein synthesis inhibitor cycloheximide, which dramatically desensitized cells to PI-induced apoptosis. Thus, similar to multiple myeloma, ALL cells are sensitive to PIs and IPIs due to increased proteotoxic stress caused by elevated rates of protein synthesis.

These results suggest that ONX-0914 prevents the internal destructive cleavage of WT1235 by IP, thereby promoting the specific presentation of the WT1 epitope by MESO-4. In conclusion, selective IP inhibitors might offer a means to modulate cancer cell immunogenicity by directing the presentation of particular tumor epitopes.

These results suggest that pharmacological inhibition of the immunoproteasome may be useful in treating metastatic gastric cancers.

We define a critical role of the immunoproteasome in CRPC and propose immunoproteasome inhibition as a promising therapeutic approach to suppress CRPC progression.

In this paper, we applied the protein homeostasis disruptors bortezomib (BTZ), ONX0914, RA190 and PR619 to various MM cell lines and primary patient samples to investigate their ability to induce immunogenic cell death (ICD). The immunological relevance of blocking de-ubiquitination in MM was further reflected by the ability of PR619-induced apoptotic cells to facilitate dendritic cell (DC) maturation via type I IFN-dependent mechanisms. Altogether, our findings identify de-ubiquitination inhibition as a promising strategy for inducing ICD of MM to expand current available treatments.

The anti-tumor effect of immunoproteasome inhibitor ONX 0914 was tested in mouse and human PC cells and the in vivo therapeutic efficacy of immunoproteasome inhibition was analyzed in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice in preventive and therapeutic settings and in castration-resistant (CR)PC after castration...Thus, immunoproteasome inhibition shows remarkable efficacy against PC progression in vivo and impedes tumor recurrence in CRPC-TRAMP mice by blocking the immunosuppressive inflammatory response in the tumor microenvironment. In conclusion, we show that the immunoproteasome is a promising drug target for the treatment of PC.

In an orthotopic mouse model, TMZ plus ONX-0914 reduced tumor progression better than the control or TMZ alone. These data suggest that ONX-0914 is a novel therapeutic drug for glioblastoma.

Inhibition of immunoproteasome with ONX-0914 suppressed activity of immunoproteasome and synergized with venetoclax against primary CLL cells. Inhibition of p38 MAPK or immunoproteasome triggered apoptosis in CLL cells and overcame the resistance to venetoclax of MEC-1 VER cells and venetoclax-insensitive primary CLL cells. In conclusion, the p38 MAPK pathway and immunoproteasome represent novel targets to combat venetoclax resistance in CLL.

Surprisingly, PR957 alone had no effects on the neuroinflammation response and the activation of TGFβ/Smad signaling in the sham-operated (BCAS-nonoperated) mice. The possible mechanism underlying this was attributed to that the immunoproteasome regulates TGFβ/Smad signaling-mediated neuroinflammation and oligodendrocyte remyelination.