DCZ0415 induces antimyeloma activity in vitro, in vivo and in primary cells of drug-resistant myeloma patients. DCZ0415 is a potent TRIP13 inhibitor that can impair the repair of non-homologous end junctions and inhibit NF-κB activity.

DCZ0415 demonstrated significant anti-proliferative effects: it reduced colony formation at 10-20 μM (72 hours), decreased MM cell viability in a dose-dependent manner at 1.25-40 μM (72 hours), increased apoptotic cell death at 10-20 μM (24-72 hours), induced G0/G1 cell cycle arrest at 10-20 μM (24 hours), and reduced protein levels of phosphorylated (p)-iκBα and phosphorylated (p)-NF-κB at 10 μM (48 hours). The IC50 in MM cell lines was 1.0–10 μM, and DCZ0415 exerted cytotoxicity by inhibiting DNA synthesis in MM cells.

DCZ0415, was confirmed to bind TRIP13 using pull-down, nuclear magnetic resonance spectroscopy, and surface plasmon resonance-binding assays.?DCZ0415 induced antimyeloma activity in vitro, in vivo, and in primary cells derived from drug-resistant patients with myeloma.?The inhibitor impaired nonhomologous end joining repair and inhibited NF-κB activity.?Moreover, combining DCZ0415 with the multiple myeloma chemotherapeutic melphalan or the HDAC inhibitor panobinostat induced synergistic antimyeloma activity.?Therefore, targeting TRIP13 may be an effective therapeutic strategy for multiple myeloma, particularly refractory or relapsed multiple myeloma.