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K858, a Novel Inhibitor of Mitotic Kinesin Eg5 and Antitumor Agent, Induces Cell Death in Cancer Cells

¹ Drug Discovery Research Laboratories, ² Pharmacological Research Laboratories, ³ Toxicological Research Laboratories, ⁴ Medicinal Chemistry Research Laboratories, Research Division, and ⁵ Clinical Development Department 1, Development Division, Kyowa Hakko Kirin Co., Ltd., Shizuoka, Japan; ⁶ Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; and ⁷ Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan

Requests for reprints: Ryuichiro Nakai, Drug Discovery Research Laboratories, Kyowa Hakko Kirin Co., Ltd, 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8731 Japan. Phone: 81-55-989-2004; Fax: 81-55-986-7430; E-mail: ryuichiro.nakai{at}kyowa-kirin.co.jp.

Key Words: antitumor agent • mitotic kinesin Eg5

The aim of this study was to investigate the mechanism of inhibition of Eg5 (kinesin spindle protein), a mitotic kinesin that plays an essential role in establishing mitotic spindle bipolarity, by the novel small molecule inhibitor K858. K858 was selected in a phenotype-based forward chemical genetics screen as an antimitotic agent, and subsequently characterized as an inhibitor of Eg5. K858 blocked centrosome separation, activated the spindle checkpoint, and induced mitotic arrest in cells accompanied by the formation of monopolar spindles. Long-term continuous treatment of cancer cells with K858 resulted in antiproliferative effects through the induction of mitotic cell death, and polyploidization followed by senescence. In contrast, treatment of nontransformed cells with K858 resulted in mitotic slippage without cell death, and cell cycle arrest in G₁ phase in a tetraploid state. In contrast to paclitaxel, K858 did not induce the formation of micronuclei in either cancer or nontransformed cells, suggesting that K858 has minimal effects on abnormalities in the number and structure of chromosomes. K858 exhibited potent antitumor activity in xenograft models of cancer, and induced the accumulation of mitotic cells with monopolar spindles in tumor tissues. Importantly, K858, unlike antimicrotubule agents, had no effect on microtubule polymerization in cell-free and cell-based assays, and was not neurotoxic in a motor coordination test in mice. Taken together, the Eg5 inhibitor K858 represents an important compound for further investigation as a novel anticancer therapeutic. [Cancer Res 2009;69(9):3901–9]

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