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

• Published in: Investigational new drugs 2010-12, Vol.28 (6), p.715-728
• Main Authors: Zhang, Zhixiang, Meng, Tao, He, Jingxue, Li, Ming, Tong, Lin-Jiang, Xiong, Bing, Lin, Liping, Shen, Jingkang, Miao, Ze-Hong, Ding, Jian
• Format: Article
• Language: English
• Subjects: Antimitotic Agents - chemistry; Antimitotic Agents - pharmacology; Apoptosis - drug effects; Cell division; Cell Line, Tumor; Cell Proliferation - drug effects; Combinatorial Chemistry Techniques; Drug Screening Assays, Antitumor; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - drug effects; Genes, Neoplasm - genetics; Heterocyclic Compounds, 4 or More Rings - chemistry; Heterocyclic Compounds, 4 or More Rings - pharmacology; Humans; Kinases; Medicine; Medicine & Public Health; Microtubules - drug effects; Microtubules - metabolism; Mitosis - drug effects; Oncology; Pharmacology/Toxicology; Polymerization; Preclinical Studies; Proteins; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Spindle Apparatus - drug effects; Spindle Apparatus - metabolism; Tubulin - metabolism; Up-Regulation - drug effects
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-009-9303-z

Summary Targeting cellular mitosis is an attractive antitumor strategy. Here, we reported MT7, a novel compound from the 6 H -Pyrido[2′,1′:2,3]imidazo [4,5- c ]isoquinolin- 5(6 H )-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.