MPI-0479605 is a potent and selective Mps1 inhibitor with IC50 value of 1.8nM. MPI-0479605 triggered the time-dependent degradation of both cyclin B and securin, which normally allow for mitotic exit, as well as a decrease in BubR1 phosphorylation in nocodazole-arrested cells, which led cells exiting mitosis and failure to undergo cytokinesis. MPI-0479605 at concentration>1.67μM blocked apparent autophosphorylation of Mps1 at threonine 676 in HEK293T cells overexpressing Mps1. Cells treated with MPI-0479605 undergo aberrant mitosis, resulting in aneuploidy and formation of micronuclei. In cells with wild-type p53, this promotes the induction of a postmitotic checkpoint characterized by the ATM- and RAD3-related-dependent activation of the p53–p21 pathway. Administration of MPI-0479605 at 30 mg/kg daily or 150 mg/kg every fourth day, i.p., for a period of 21 days, inhibited tumor growth of mice bearing subcutaneous HCT-116 tumor cell xenografts[2].
作用机制
MPI-0479605 is an ATP competitive inhibitor of Mps1.[2]
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