MT119, a new planar-structured compound, targets the colchicine site of tubulin arresting mitosis and inhibiting tumor cell proliferation
文献类型：期刊论文
| 作者 | Zhang, Zhixiang1; Meng, Tao2 ; Yang, Na1; Wang, Wei1; Xiong, Bing2; Chen, Yi1; Ma, Lanping2; Shen, Jingkang2; Miao, Ze-Hong1; Ding, Jian1
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| 刊名 | INTERNATIONAL JOURNAL OF CANCER
 |
| 出版日期 | 2011-07-01 |
| 卷号 | 129期号:1页码:214-224 |
| 关键词 | mitosis tubulin the colchicine site spindle assembly |
| ISSN号 | 0020-7136 |
| DOI | 10.1002/ijc.25661 |
| 文献子类 | Article |
| 英文摘要 | Microtubule-targeted drugs are now indispensable for the therapy of various cancer types worldwide. In this article, we report MT119 [6-[2-(4-methoxyphenyl) -ethyl]-9-[(pyridine-3-ylmethyl)amino]pyrido[2',1': 2,3]imida-zo[4,5-c]isoquinolin-5(6H)-one] as a new microtubule-targeted agent. MT119 inhibited tubulin polymerization significantly both in tumor cells and in cell-free systems, which was followed by the disruption of mitotic spindle assembly. Surface plasmon resonance-based analyses showed that MT119 bound to purified tubulin directly, with the K(D) value of 10.6 mu M. The binding of MT119 in turn caused tubulin conformational changes as evidenced by the quenched tryptophan fluorescence, the reduction of the bis-ANS reactivity and the decreased DTNB-sulfhydryl reaction rate. Competitive binding assays further revealed that MT119 bound to tubulin at its colchicine site. Consequently, by inhibiting tubulin polymerization, MT119 arrested different tumor cells at mitotic phase, which contributed to its potent antitumor activity in vitro. MT119 was also similarly cytotoxic to vincristine-, adriamycin-or mitoxantrone-resistant cancer cells and to their corresponding parental cells. Together, these data indicate that MT119 represents a new class of colchicine-site-targeted inhibitors against tubulin polymerization, which might be a promising starting point for future cancer therapeutics. |
| WOS关键词 | SPINDLE ASSEMBLY CHECKPOINT ; ISOTHERMAL TITRATION CALORIMETRY ; COMBRETASTATIN A4 PHOSPHATE ; I CLINICAL-EVALUATION ; TOPOISOMERASE-II ; SOLID TUMORS ; AGENT ; APOPTOSIS ; BINDING ; POLYMERIZATION |
| 资助项目 | National Natural Science Foundation of China (NSFC)[30873092] ; National Natural Science Foundation of China (NSFC)[30721005] ; National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program'' of China[2009ZX09103-074] ; National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program'' of China[2009ZX09301-001] ; The Science, Technology Commission of Shanghai Municipality (STCSM)[08PJ14113] ; National Basic Research Program of China[2010CB934000] |
| WOS研究方向 | Oncology |
| 语种 | 英语 |
| WOS记录号 | WOS:000289987300021 |
| 出版者 | WILEY-BLACKWELL |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/278492]  |
| 专题 | 药理学第一研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Ding, Jian |
| 作者单位 | 1.Chinese Acad Sci, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Dept Med Chem, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhang, Zhixiang,Meng, Tao,Yang, Na,et al. MT119, a new planar-structured compound, targets the colchicine site of tubulin arresting mitosis and inhibiting tumor cell proliferation[J]. INTERNATIONAL JOURNAL OF CANCER,2011,129(1):214-224. |
| APA | Zhang, Zhixiang.,Meng, Tao.,Yang, Na.,Wang, Wei.,Xiong, Bing.,...&Ding, Jian.(2011).MT119, a new planar-structured compound, targets the colchicine site of tubulin arresting mitosis and inhibiting tumor cell proliferation.INTERNATIONAL JOURNAL OF CANCER,129(1),214-224. |
| MLA | Zhang, Zhixiang,et al."MT119, a new planar-structured compound, targets the colchicine site of tubulin arresting mitosis and inhibiting tumor cell proliferation".INTERNATIONAL JOURNAL OF CANCER 129.1(2011):214-224. |
入库方式： OAI收割
来源：上海药物研究所
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