Description
MPI-0479605 is a potent and ATP-competitive inhibitor of the mitotic kinase MPS1 (IC
50 = 1.8 nM). It is selective for MPS1 over a panel of 79 kinases at a concentration of 500 nM. MPI-0479605 induces time-dependent degradation of cyclin B and securin and decreases phosphorylation of BUBR1 resulting in failed cytokinesis in HeLa cells arrested by nocodazole . It also causes misalignment of chromosomes at the anaphase plate and aneuploidy in A549 cells and slows cell cycle progression of HCT116 and COLO 205 cells irrespective of p53 activity. MPI-0479605 (30-150 mg/kg) reduces tumor volume in an HCT116 mouse colon cancer xenograft model in a dose-dependent manner.
Uses
MPI-0479605 is a potent and selective ATP-competitive inhibitor of Mps1, with an IC50 of 1.8 nM.
in vivo
MPI-0479605 (30 mg/kg daily or 150 mg/kg every fourth day (Q4D), i.p.) inhibits tumor growth by 49% and 74 % in HCT-116 xenografts. However, MPI-0479605 does not show inhibitory activity via daily dosing on the Colo-205 xenografts, and dosing every four days causes 63% tumor growth inhibition (TGI)[1].
IC 50
Mps1: 1.8 nM (IC
50); ALK: 0.26 μM (IC
50); B-RAF: 3.2 μM (IC
50); ERK2: 3.9 μM (IC
50); FAK1: 2.7 μM (IC
50); FER: 0.59 μM (IC
50); FLT3: 0.08 μM (IC
50); INSR: 0.38 μM (IC
50); JNK1: 0.11 μM (IC
50); PLK4: 3.3 μM (IC
50); STK33: 1.1 μM (IC
50)
References
[1] tardif k d, rogers a, cassiano j, et al. characterization of the cellular and antitumor effects of mpi-0479605, a small-molecule inhibitor of the mitotic kinase mps1. molecular cancer therapeutics, 2011, 10(12): 2267-2275.
