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.

Details

Title
Identification of candidate molecular targets of the novel antineoplastic antimitotic NP-10
Author
Yokoyama, Takuya 1 ; Yukuhiro, Masaki 1 ; Iwasaki, Yuka 1 ; Tanaka, Chika 1 ; Sankoda, Kazunari 1 ; Fujiwara, Risa 2 ; Shibuta, Atsushi 2 ; Higashi, Taishi 3 ; Motoyama, Keiichi 4 ; Arima, Hidetoshi 5 ; Yoshida, Kazumasa 1 ; Sugimoto, Nozomi 1 ; Morimoto, Hiroyuki 2 ; Kosako, Hidetaka 6 ; Ohshima, Takashi 2 ; Fujita, Masatoshi 1 

 Department of Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashiku, Fukuoka, Japan 
 Department of Green Pharmaceutical Chemistry, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashiku, Fukuoka, Japan 
 Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan; Priority Organization for Innovation and Excellence, Kumamoto University, Chuo-ku, Kumamoto, Japan 
 Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan 
 Laboratory of Evidence-Based Pharmacotherapy, Daiichi University of Pharmacy, Minami-ku, Fukuoka, Japan 
 Division of Cell Signaling, Fujii Memorial Institute of Medical Sciences, Tokushima University, Tokushima, Japan 
Pages
1-13
Publication year
2019
Publication date
Nov 2019
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2314539966
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.