Background:

K858 Racemic is an ATP-uncompetitive inhibitor of kinesin Eg5 with an IC50 of 1.3 μM.

K858 Racemic is an ATP-uncompetitive inhibitor of Eg5 with an IC50 of 1.3 μM. K858 does not inhibit the ATPase activity of the mitotic kinesins CENP-E and MKLP1, or the conventional kinesin heavy chain even at 200 μM. K858 induces mitotic arrest and growth inhibition via the activation of the Mad2-mediated spindle checkpoint. K858 (5 μM) induces mitotic cell death in cancer cells but not in normal cells[1]. K858 (1, 10, 100 μM) inhibits the MCF7, BT474 and SKBR3 cell lines, and only at 10 and 100 μM suppresses MDA-MB231 cell line after treatment for 24 h. K858 incereases Bax/Bcl2 RNA ratio and survivin in the four cell lines. Furthermore, the up-regulation of survivin is totally reversed by wortmannin (phosphoinositide 3-kinase AKT) in MCF7 cells[2].

K858 (50, 150 mg/kg, p.o.) shows antitumor activity in an A2780 ovarian cancer xenograft model, also inhibits tumor grwoth in a HCT116 colon cancer xenograft model via 100 mg/kg twice a day orally for 5 days. K858 (100 mg/kg, p.o., qd ×5) displays no neurotoxic side effects in mice[1].

参考文献:
[1]. Nakai R, et al. K858, a novel inhibitor of mitotic kinesin Eg5 and antitumor agent, induces cell death in cancer cells. Cancer Res. 2009 May 1;69(9):3901-9.
[2]. De Iuliis F, et al. The kinesin Eg5 inhibitor K858 induces apoptosis but also survivin-related chemoresistance in breast cancer cells. Invest New Drugs. 2016 Aug;34(4):399-406.