Inhibition of NF-kB DNA Binding Suppresses Myeloma Growth via Intracellular Redox and Tumor Microenvironment Modulation

Multiple myeloma is a plasma cell malignancy that is still largely IT848 treatment altered the redox homeostasis of multiple myeloma incurable, despite considerable progress in recent years. NF-kB is a cells through depletion of the reduced glutathione pool, selecwell-established therapeutic target in multiple myeloma, but none tively inducing oxidative stress in multiple myeloma but not in of the currently available treatment options offer direct, specific healthy cells. Multiple myeloma xenograft studies confirmed the pharmacologic targeting of NF-kB transcriptional activity. Thus, we efficacy of IT848 as single agent and in combination with designed a novel direct NF-kB inhibitor (IT848) as a drug candidate bortezomib. Furthermore, IT848 significantly improved survival with strong potential for clinical translation and conducted com-when combined with programmed death protein 1 inhibition, prehensive in vitro and in vivo mechanistic studies in multiple and correlative immune studies revealed that this clinical benefit myeloma cell lines, primary multiple myeloma cells, xenograft was associated with suppression of regulatory T-cell infiltration models, and immunocompetent mouse models of multiple myeof the bone marrow microenvironment. In conclusion, IT848 is a loma. Here, we show that IT848 inhibits NF-kB activity through potent direct NF-kB inhibitor and inducer of oxidative stress inhibition of DNA binding of all five NF-kB subunits. IT848 specifically in tumor cells, displaying significant activity against treatment of multiple myeloma cell lines and patient samples multiple myeloma cells in vitro and in vivo, both as monotherapy inhibited proliferation and induced caspase-dependent and indeas well as in combination with bortezomib or immune check-pendent apoptosis. In addition to direct NF-kB inhibitory effects, point blockade.