Supinoxin (RX-5902)

Supinoxin-treated cells exhibited marked mitochondrial dysfunction, supporting the hypothesis that DDX5 inhibition disrupts cellular energy metabolism. These findings illuminate a previously underappreciated role of DDX5 in mitochondrial regulation and offer mechanistic insights into Supinoxin's cytotoxic effects, underscoring its potential as a targeted therapy in SCLC.

Finally, we find that Supinoxin inhibits expression of mitochondrial genes and effectively blocks respiration. These studies suggest that Supinoxin functions in anti-tumor progression by reducing cellular energy levels through DDX5.

Indeed, concurrent treatment using RX-5902 and Venetoclax, a BCL-2 inhibitor, synergistically induced apoptosis in AML cells. Collectively, therapeutic targeting of DDX5 may be a novel and effective approach in AML and warrants further study.

RX-5902 enhanced the efficacy of nivolumab in a humanized, preclinical model of TNBC. Several changes in immunologic profiles were noted in mice treated with RX-5902 and the combination, including an increase in activated TILs and a decrease in human myeloid populations, that are often associated with immunosuppression in a tumor microenvironment. RX-5902 also was shown to potentiate the effects of checkpoint inhibitors of CTLA4 and the PD-1 inhibitor in the 4 T-1 murine TNBC model. These findings indicate that RX-5902 may have important immunomodulatory, as well as anti-tumor activity, in TNBC when combined with a checkpoint inhibitor.

Target engagement was confirmed with decreases in nuclear β-catenin and MCL-1 observed, confirming the proposed mechanism of action. This study supports the continued investigation of RX-5902 in TNBC and combinations with immunotherapy.