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01-12-2010 | PRECLINICAL STUDIES

MT7, a novel compound from a combinatorial library, arrests mitosis via inhibiting the polymerization of microtubules

Authors: Zhixiang Zhang, Tao Meng, Jingxue He, Ming Li, Lin-Jiang Tong, Bing Xiong, Liping Lin, Jingkang Shen, Ze-Hong Miao, Jian Ding

Published in: Investigational New Drugs | Issue 6/2010

Summary

Targeting cellular mitosis is an attractive antitumor strategy. Here, we reported MT7, a novel compound from the 6H-Pyrido[2′,1′:2,3]imidazo [4,5-c]isoquinolin- 5(6H)-one library generated by using the multi-component reaction strategy, as a new mitotic inhibitor. MT7 elicited apparent inhibition of cell proliferation by arresting mitosis specifically and reversibly in various tumor cell lines originating from different human tissues. Detailed mechanistic studies revealed that MT7 induced typical gene expression profiles related to mitotic arrest shown by cDNA microarray assays. Connectivity Map was used to analyze the microarray data and suggested that MT7 was possibly a tubulin inhibitor due to its similar gene expression profiles to those of the known tubulin inhibitors demecolcine, celastrol and paclitaxel. Further analyses demonstrated that MT7 inhibited the polymerization of cellular microtubules although it was not detectable to bind to purified tubulin. The inhibition of cellular tubulin polymerization by MT7 subsequently resulted in the disruption of mitotic spindle formation, activated the spindle assembly checkpoint and consequently arrested the cells at mitosis. The persistent mitotic arrest by the treatment with MT7 led the tested tumor cells to apoptosis. Our data indicate that MT7 could act as a promising lead for further optimization, in hopes of developing new anticancer therapeutics and being used to probe the biology of mitosis, specifically, the mode of interference with microtubules.

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Title: MT7, a novel compound from a combinatorial library, arrests mitosis via inhibiting the polymerization of microtubules
Authors: Zhixiang Zhang
Tao Meng
Jingxue He
Ming Li
Lin-Jiang Tong
Bing Xiong
Liping Lin
Jingkang Shen
Ze-Hong Miao
Jian Ding
Publication date: 01-12-2010
Publisher: Springer US
Published in: Investigational New Drugs / Issue 6/2010
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-009-9303-z

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