MPS1 (monopolar spindle 1, also known as TTK) is a dual specificity kinase that occupies a central role in mitosis. MPS1 is one of the main components of the spindle assembly checkpoint (SAC)1−4 and ensures cells do not progress from metaphase to anaphase until the kinetochores are properly attached to the microtubules and under the appropriate tension at the metaphase plate. Cancer cells heavily rely on MPS1 to cope with aneuploidy resulting from aberrant numbers of chromosomes[2]. High MPS1 was associated with poorer long term survival when all gliomas were analyzed combined in one group (Cox regression: t < 24 months, p = 0.009, Hazard ratio: 8.0, 95% CI: 1.7-38.4), with poorer survival solely in low-grade gliomas (LogRank: p = 0.02, Cox regression: p = 0.06, Hazard-Ratio: 8.0, 95% CI: 0.9-66.7), but not in GBM (LogRank: p > 0.05)[3]. BOS-172722 is an inhibitor of monopolar spindle 1 (MPS1) checkpoint with an IC50 of 2 nM and it also has potential for the treatment of various forms of breast cancer[4]. In in vivo pharmacodynamic experiments, BOS172722 potently inhibits the spindle assembly checkpoint induced by paclitaxel in human tumor xenograft models of TNBC, as measured by inhibition of the phosphorylation of histone H3 and the phosphorylation of the MPS1 substrate, KNL1. This mechanistic synergy results in significant in vivo efficacy, with robust tumor regressions observed for the combination of BOS172722 and paclitaxel versus either agent alone in long-term efficacy studies in multiple human tumor xenograft TNBC models, including a patient-derived xenograft and a systemic metastasis model[5].
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