BACKGROUND: The main role of the cell cycle is to enable error-free DNA 
replication, chromosome segregation and cytokinesis. One of the best 
characterised checkpoint pathways is the spindle assembly checkpoint, which 
prevents anaphase onset until the appropriate attachment and tension across 
kinetochores is achieved. MPS1 kinase activity is essential for the activation 
of the spindle assembly checkpoint and has been shown to be deregulated in human 
tumours with chromosomal instability and aneuploidy. Therefore, MPS1 inhibition 
represents an attractive strategy to target cancers.
METHODS: To evaluate CCT271850 cellular potency, two specific antibodies that 
recognise the activation sites of MPS1 were used and its antiproliferative 
activity was determined in 91 human cancer cell lines. DLD1 cells with induced 
GFP-MPS1 and HCT116 cells were used in in vivo studies to directly measure MPS1 
inhibition and efficacy of CCT271850 treatment.
RESULTS: CCT271850 selectively and potently inhibits MPS1 kinase activity in 
biochemical and cellular assays and in in vivo models. Mechanistically, tumour 
cells treated with CCT271850 acquire aberrant numbers of chromosomes and the 
majority of cells divide their chromosomes without proper alignment because of 
abrogation of the mitotic checkpoint, leading to cell death. We demonstrated a 
moderate level of efficacy of CCT271850 as a single agent in a human colorectal 
carcinoma xenograft model.
CONCLUSIONS: CCT271850 is a potent, selective and orally bioavailable MPS1 
kinase inhibitor. On the basis of in vivo pharmacodynamic vs efficacy 
relationships, we predict that more than 80% inhibition of MPS1 activity for at 
least 24 h is required to achieve tumour stasis or regression by CCT271850.