DCZ0415

DCZ0415 is a small molecule inhibitor of Thyroid hormone receptor interactor 13 (TRIP13), an AAA+ ATPase that plays a critical role in the spindle assembly checkpoint (SAC) and DNA repair. TRIP13 is responsible for converting the closed conformation of MAD2 (C-MAD2) to the open conformation (O-MAD2), a process essential for the disassembly of the mitotic checkpoint complex (MCC) and subsequent mitotic exit. DCZ0415 binds to TRIP13 and selectively interferes with this MAD2 conversion without significantly affecting TRIP13's ATPase activity. This inhibition leads to the persistence of the SAC, resulting in mitotic catastrophe and apoptosis, particularly in Rb-deficient cancer cells that exhibit a dependency on TRIP13 for proper mitotic progression. Preclinical studies in lung cancer models indicate that DCZ0415 can enhance antitumor immunity by increasing T-cell infiltration and reducing immunosuppressive myeloid-derived suppressor cells (MDSCs), especially when used in combination with Aurora kinase A inhibitors like alisertib.