BAY 1217389

Biological Activity

BAY 1217389 selectively binds to and inhibits the activity of Mps1. This inactivates the spindle assembly checkpoint (SAC), accelerates mitosis, causes chromosomal misalignment and missegregation, and mitotic checkpoint complex destabilization. This induces cell death in Mps1-overexpressing cancer cells. BAY 1217389 efficiently inhibits tumor cell proliferation in vitro.

In vivo: BAY 1217389 achieves moderate efficacy in monotherapy in tumor xenograft studies. However, in line with its unique mode of action, when combines with paclitaxel, low doses of Mps1 inhibitor reduces paclitaxel-induced mitotic arrest in line with weakening of SAC activity. As a result, combination therapy strongly improves efficacy over paclitaxel or Mps1 inhibitor monotreatment at the respective MTDs in a broad range of xenograft models including those showing acquired or intrinsic paclitaxel-resistance. BAY 1217389 shows good tolerability without adding toxicity to paclitaxel monotherapy.

Protocol (for reference only)

Cell Experiment
Cell lines	Tumor cell lines HeLa-MaTu and HeLa-MaTu-ADR cells
Preparation method	Cells were seeded into 96-well plates at densities ranging from 1,000 to 5,000 cells per well in the appropriate medium supplemented with 10% FCS. After 24 hours, cells were treated in quadruplicates with serial dilutions of compounds. After further 96 hours, adherent cells were fixed with glutaraldehyde and stained with crystal violet. IC50 values were calculated by means of a 4-parameter fit using the company's own software.
Concentrations
Incubation time	96 h

Animal Experiment
Animal models	Male Wistar rats and female CD1 or NMRI nu/nu mice
Formulation	50% PEG 400, 10% ethanol, and 40% water
Dosages	1, 2, 4, or 8 mg/kg (p.o.)
Administration	i.v. or p.o.

Chemical Information

Molecular Weight	561.5
Formula	C27H24F5N5O3
CAS Number	1554458-53-5
Solubility (25°C)	DMSO: ≥ 60 mg/mL
Storage	Powder          -20°C   3 years ;  4°C   2 years In solvent       -80°C   6 months ;  -20°C   1 month

Conversion of different model animals based on BSA (PMID: 27057123)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km factor	3	6	12	8	5	20

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.

References

[1] Wengner AM, et al. Mol Cancer Ther. Novel Mps1 Kinase Inhibitors with Potent Antitumor Activity.