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.
|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.|
|Incubation time||96 h|
|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.|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO: ≥ 60 mg/mL|
Novel Mps1 Kinase Inhibitors with Potent Antitumor Activity.
Wengner AM, et al. Mol Cancer Ther. 2016 Apr;15(4):583-92. PMID: 26832791.
|Related Kinesin Products|
ARQ 621 is an allosteric, and selective Eg5 mitotic motor protein inhibitor.
EMD534085 is a potent and selective inhibitor of the mitotic kinesin-5 with an IC50 of 8 nM.
Eg5 is a key protein involved in the formation of bipolar spindles.
Monastrol is a cell-permeable small molecule inhibitor of kinesin-5(KIF11) which is essential for maintaining separation of the half-spindles.
AZD4877 is a synthetic kinesin spindle protein (KSP) inhibitor with potential antineoplastic activity.
Products are for research use only. Not for human use. We do not sell to patients.
© Copyright 2010-2020 AbMole BioScience. All Rights Reserved.