EMD534085 is a potent and selective inhibitor of the mitotic kinesin-5 with an IC50 of 8 nM. EMD534085 induces rapid cell death in HL60 during mitotic arrest. Caspase-8, −9, −3, −7 are activated; Parp1 is cleaved; Mcl1 and XIAP are degraded in EMD534085-treated HL60 cells. EMD534085 treated HL60 cells also shows significantly accumulated phospho-Histone H3 level starting at 6 hrs post thymidine release.
In vivo: In a low dose PK of EMD 534085 in mice the clearance is 1.8 L/h/kg on average, the volume of distribution is 7.4 L/kg and the half life around 2.5 h. The bioavailability in high dose experiments (>10 mg/kg) is always above 50% in mice. Intraperitonal administration of EMD 534085 enables significant systemic exposure in mice leading to a significant tumor growth reduction without toxic side effects.
|Cell lines||Epithelial cell lines HeLa and MCF7|
|Preparation method||Epithelial cell lines HeLa and MCF7 are synchronized in G2-phase using RO-3306. Cells are treated with 10 µM RO-3306 for 16 hrs, and then are ished and released to either warm growth medium or medium supplemented with 500 nM EMD534085.|
|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: ≥ 20 mg/mL|
Prolonged mitotic arrest triggers partial activation of apoptosis, resulting in DNA damage and p53 induction.
Orth JD, et al. Mol Biol Cell. 2012 Feb;23(4):567-76. PMID: 22171325.
Rapid induction of apoptosis during Kinesin-5 inhibitor-induced mitotic arrest in HL60 cells.
Tang Y, et al. Cancer Lett. 2011 Nov 1;310(1):15-24. PMID: 21782324.
The discovery and optimization of hexahydro-2H-pyrano[3,2-c]quinolines (HHPQs) as potent and selective inhibitors of the mitotic kinesin-5.
Schiemann K, et al. Bioorg Med Chem Lett. 2010 Mar 1;20(5):1491-5. PMID: 20149654.
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