Functional characterization of CFI-402257, a potent and selective Mps1/TTK kinase inhibitor, for the treatment of cancer

Significance At present, microtubule-targeting agents are the most important antimitotic drugs used in the clinic. However, there is an urgent need for the discovery of new approaches to more effectively target tumor cells with less toxicity. Emerging strategies for anticancer therapy include exploiting cell-cycle checkpoint vulnerabilities and genomic instability in cancer cells. The spindle assembly checkpoint (SAC) is important for cell survival, and its inactivation generates lethal genomic instability in cancer cells. Inhibition of SAC signaling through targeting of monopolar spindle 1 (Mps1) has provided an indication of the feasibility of such an approach. We report here the cellular and antitumor effects of CFI-402257, a potent and specific small-molecule inhibitor of Mps1. CFI-402257 is currently in a phase I clinical trial ( ClinicalTrials.gov ID: NCT02792465).