MPI-0479605 Chemical Properties

Boiling point:

745.8±70.0 °C(Predicted)

Density 

1.318±0.06 g/cm3(Predicted)

storage temp. 

Keep in dark place,Inert atmosphere,Store in freezer, under -20°C

solubility 

Soluble in DMSO

form 

A crystalline solid

pka

10.52±0.10(Predicted)

color 

White to gray

MPI-0479605 Usage And Synthesis

Description

MPI-0479605 is a potent and ATP-competitive inhibitor of the mitotic kinase MPS1 (IC₅₀ = 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.

Synthesis

The general procedure for the synthesis of N6-cyclohexyl-N2-(2-methyl-4-morpholinophenyl)-9H-purine-2,6-diamine from compound (CAS:39639-45-7) and compound (CAS:1246532-35-3) was as follows: compound 1 (2.00 g, 7.91 mmol) was mixed with compound 4 (2.53 g, 9.56 mmol), sodium acetate (980 mg, 11.95 mmol) and chloroform (40 mL) in an 80 mL microwave reaction flask to form a suspension. Subsequently, the mixture was heated to 150 °C in a microwave reactor and maintained for 30 min. Upon completion of the reaction, the solvent was removed by distillation under reduced pressure. The resulting crude product was purified by reversed-phase medium pressure liquid chromatography (MPLC) to give a final white solid product in 12-30% yield.

in vivo

IC 50

Mps1: 1.8 nM (IC₅₀); ALK: 0.26 μM (IC₅₀); B-RAF: 3.2 μM (IC₅₀); ERK2: 3.9 μM (IC₅₀); FAK1: 2.7 μM (IC₅₀); FER: 0.59 μM (IC₅₀); FLT3: 0.08 μM (IC₅₀); INSR: 0.38 μM (IC₅₀); JNK1: 0.11 μM (IC₅₀); PLK4: 3.3 μM (IC₅₀); STK33: 1.1 μM (IC₅₀)

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.

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