AZ3146

AZ3146 is a potent and selective small molecule inhibitor of Monopolar spindle 1 (Mps1), also known as TTK protein kinase. Mps1 is a critical component of the spindle assembly checkpoint (SAC) that ensures proper chromosome attachment and alignment during mitosis. By inhibiting Mps1, AZ3146 induces severe chromosome mis-segregation and aneuploidy, leading to high levels of chromosome instability (CIN). In preclinical models of acute myeloid leukemia (AML), AZ3146 treatment has been shown to trigger immunogenic cell death (ICD), characterized by the exposure of calreticulin and the release of danger signals that activate innate immune cells such as natural killer (NK) cells and dendritic cells. Furthermore, AZ3146 induces DNA damage and upregulates PD-L1 expression, suggesting its potential utility in combination with checkpoint inhibitor immunotherapies to enhance therapeutic efficacy in hematological malignancies.