TY - JOUR
T1 - Identification of candidate molecular targets of the novel antineoplastic antimitotic NP-10
AU - Yokoyama, Takuya
AU - Yukuhiro, Masaki
AU - Iwasaki, Yuka
AU - Tanaka, Chika
AU - Sankoda, Kazunari
AU - Fujiwara, Risa
AU - Shibuta, Atsushi
AU - Higashi, Taishi
AU - Motoyama, Keiichi
AU - Arima, Hidetoshi
AU - Yoshida, Kazumasa
AU - Sugimoto, Nozomi
AU - Morimoto, Hiroyuki
AU - Kosako, Hidetaka
AU - Ohshima, Takashi
AU - Fujita, Masatoshi
N1 - Funding Information:
We thank Dr. Masao Seto for providing HEK293T cells. We also thank Ms. Chinasa Sueyoshi (Kyushu University) for technical and secretarial assistance, Dr. Naoki Tani (Kumamoto University) for technical assistance with LC-MS/MS analysis, and Ms. Pang Nisha, Ms. Bei Liu, and Dr. Kenji Watanabe (Kyushu University) for the synthesis of NP-10 derivatives. We are grateful to the Research Support Center, Graduate School of Medical Sciences, Kyushu University, for technical support. This work was supported in part by Platform Project for Supporting Drug Discovery and Life Science Research [Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)] from AMED under Grant Number JP18am0101091, and by grants to H.K. from the program to the Joint Usage/Research Center for Developmental Medicine, Institute of Molecular Embryology and Genetics, Kumamoto University.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41598-019-53259-2
DO - 10.1038/s41598-019-53259-2
M3 - Article
C2 - 31727981
AN - SCOPUS:85075058421
SN - 2045-2322
VL - 9
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 16825
ER -
