Background:

EMD534085 is a potent and selective inhibitor of the mitotic kinesin-5 with an IC50 of 8 nM.

EMD 534085 does not inhibit any other tested kinesins (BimC, CEN-PE, Chromokinesin, KHC, KIF3C, KIFC3, MKLP-1, and MCAK) at 1 μM or 10 μM concentration, showing selectively over kinesin-5. EMD 534085 binds to the allosteric pocket of kinesin-5[1]. 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[2].

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[1].

参考文献

[1]. Schiemann K, et al. The discovery and optimization of hexahydro-2H-pyrano[3,2-c]quinolines (HHPQs) as potent and selective inhibitors of the mitotic kinesin-5. Bioorg Med Chem Lett. 2010 Mar 1;20(5):1491-5.

[2]. Tang Y, et al. Rapid induction of apoptosis during Kinesin-5 inhibitor-induced mitotic arrest in HL60 cells. Cancer Lett. 2011 Nov 1;310(1):15-24.