In vitro
AZ3146 inhibits human Mps1Cat with an IC50 of 35 nM. AZ3146 also efficiently inhibited autophosphorylation of full-length Mps1 immunoprecipitated from human cells. AZ3146 is a reasonably potent and selective Mps1 inhibitor. AZ3146 overrides the spindle checkpoint. HeLa cells treated with nocodazole and 2 uM AZ3146 only delayed mitosis briefly and then rereplicated their genomes. During an otherwise unperturbed mitosis, AZ3146 reduced the time to complete mitosis from 90 min in controls to 32 min. During mitosis, Mps1 activity is required continuously to recruit Mad2 to kinetochore-bound Mad1, but AZ3146 can abolish Mad2 localization. And inhibition of Mps1 by AZ3146 can increase its abundance at kinetochores.
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