A Small Molecule Inhibitor Targeting TRIP13 suppresses multiple myeloma progression.

The AAA-ATPase TRIP13 drives multiple myeloma (MM) progression. Here we present the crystal structure of wild-type human TRIP13 at a resolution of 2.6 Å. A small molecule inhibitor targeting TRIP13 was identified based on the crystal structure. The inhibitor, designated DCZ0415, was confirmed to bind TRIP13 using pull-down, nuclear magnetic resonance spectroscopy, and surface plasmon resonance binding assays. DCZ0415 induced anti-myeloma activity in vitro, in vivo, and in primary cells derived from drug-resistant myeloma patients. The inhibitor impaired nonhomologous end joining repair and inhibited NF-κB activity. Moreover, combining DCZ0415 with the MM chemotherapeutic melphalan or the HDAC inhibitor panobinostat induced synergistic anti-myeloma activity. Therefore, targeting TRIP13 may be an effective therapeutic strategy for MM, particularly refractory or relapsed MM.