Identification of candidate molecular targets of the novel antineoplastic antimitotic NP-10

Takuya Yokoyama, Masaki Yukuhiro, Yuka Iwasaki, Chika Tanaka, Kazunari Sankoda, Risa Fujiwara, Atsushi Shibuta, Taishi Higashi, Keiichi Motoyama, Hidetoshi Arima, Kazumasa Yoshida, Nozomi Sugimoto, Hiroyuki Morimoto, Hidetaka Kosako, Takashi Ohshima, Masatoshi Fujita

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Abstract

We previously reported the identification of a novel antimitotic agent with carbazole and benzohydrazide structures: N′-[(9-ethyl-9H-carbazol-3-yl)methylene]-2-iodobenzohydrazide (code number NP-10). However, the mechanism(s) underlying the cancer cell-selective inhibition of mitotic progression by NP-10 remains unclear. Here, we identified NP-10-interacting proteins by affinity purification from HeLa cell lysates using NP-10-immobilized beads followed by mass spectrometry. The results showed that several mitosis-associated factors specifically bind to active NP-10, but not to an inactive NP-10 derivative. Among them, NUP155 and importin β may be involved in NP-10-mediated mitotic arrest. Because NP-10 did not show antitumor activity in vivo in a previous study, we synthesized 19 NP-10 derivatives to identify more effective NP-10-related compounds. HMI83-2, an NP-10-related compound with a Cl moiety, inhibited HCT116 cell tumor formation in nude mice without significant loss of body weight, suggesting that HMI83-2 is a promising lead compound for the development of novel antimitotic agents.

Original languageEnglish
Article number16825
JournalScientific reports
Volume9
Issue number1
DOIs
Publication statusPublished - Dec 1 2019

All Science Journal Classification (ASJC) codes

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    Yokoyama, T., Yukuhiro, M., Iwasaki, Y., Tanaka, C., Sankoda, K., Fujiwara, R., Shibuta, A., Higashi, T., Motoyama, K., Arima, H., Yoshida, K., Sugimoto, N., Morimoto, H., Kosako, H., Ohshima, T., & Fujita, M. (2019). Identification of candidate molecular targets of the novel antineoplastic antimitotic NP-10. Scientific reports, 9(1), [16825]. https://doi.org/10.1038/s41598-019-53259-2