Monopolar spindle 1 (Mps1/TTK) kinase is a key component of the spindle assembly checkpoint (SAC), which is essential for cell survival. CFI-402257 is orally bioavailable, highly selective inhibitor of Mps1 with an IC50 value of 1.2 ± 0.4 nM and is ATP competitive with a Ki value of 0.09 ± 0.02 nM. In cells exogenously expressing human Mps1, CFI-402257 blocked auto-phosphorylation of Mps1 at threonine 12/serine 15 with an EC50 value of 6.5 ± 0.5 nM. CFI-402257 also exerts inhibitory activity on the activation of the SAC with an IC50 value of 64 ± 5 nM. Treatment of HCT116 cells with 200 nM CFI-402257 led to a remarkable increase in chromosome missegregations compared to DMSO-treated control cells. CFI-402257 at 50 - 3000 nM increased the frequency of HCT116 cells with an aneuploid DNA content, and the massive aneuploidy was observed when cells were dosed with 100 nM CFI-402257. Moreover, CFI-402257 exhibited potent growth inhibitory effect on a vast majority of human cancer cell lines with a median IC50 value of 15 nM. In a mouse xenografted model of MDA-MB-231 human TNBC cells, daily oral administration of CFI-402257 at 5 mg/kg and 6 mg/kg for 22 days showed tumor growth inhibition (TGI) of 74% and 89%, respectively. Similar results were found in mice xenografted with MDA-MB-468 human TNBC cells (5 mg/kg, TGI = 75%; 6 mg/kg, TGI = 94%). In addition, significantly decreased number of phospho-histone H3 serine 10-positive cells per square millimeter of tumor tissue was observed in CFI-402257-treated tumors (6 mg/kg and 35 mg/kg) as compared to vehicle controls[3].
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