摘要
微管药物已经广泛用于肿瘤化疗。尽管微管受到信号转导机制的调节,目前为止所知,他们的药理调节主要依赖结合到微管蛋白亚基上的化合物。通过建立细胞模型以探测微管聚合状态,本研究确定了CM09 和CM10两个药效基团为细胞可透过性的微管稳定剂。这些合成的化合物不影响纯化的微管蛋白在体外组装状态,但在体内,他们显著地抑制微管蛋白的动力学。此外,它们对包括多药耐药肿瘤细胞在内的多种肿瘤细胞系有细胞毒性作用。因此,这类化合物对于癌症的化疗提供了新颖和有吸引力的线索。
关键词: 化学生物学;高内涵细胞成像分析技术;微管动力学;微管靶向剂;表型筛选。
Current Cancer Drug Targets
Title:Novel Synthetic Pharmacophores Inducing a Stabilization of Cellular Microtubules
Volume: 15 Issue: 1
Author(s): Anne Martinez, Emmanuelle Soleilhac, Caroline Barette, Renaud Prudent, Gustavo J. Gozzi, Emilie Vassal-Stermann, Catherine Pillet, Attilio Di Pietro, Marie-Odile Fauvarque and Laurence Lafanechere
Affiliation:
关键词: 化学生物学;高内涵细胞成像分析技术;微管动力学;微管靶向剂;表型筛选。
摘要: Microtubule drugs have been widely used in cancer chemotherapies. Although microtubules are subject to regulation by signal transduction mechanisms, their pharmacological modulation has so far relied on compounds that bind to the tubulin subunit. Using a cell-based assay designed to probe the microtubule polymerization status, we identified two pharmacophores, CM09 and CM10, as cell-permeable microtubule stabilizing agents. These synthetic compounds do not affect the assembly state of purified microtubules in vitro but they profoundly suppress microtubule dynamics in vivo. Moreover, they exert cytotoxic effects on several cancer cell lines including multidrug resistant cell lines. Therefore, these classes of compounds represent novel attractive leads for cancer chemotherapy.
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Anne Martinez , Emmanuelle Soleilhac , Caroline Barette , Renaud Prudent , Gustavo J. Gozzi , Emilie Vassal-Stermann , Catherine Pillet , Attilio Di Pietro , Marie-Odile Fauvarque and Laurence Lafanechere , Novel Synthetic Pharmacophores Inducing a Stabilization of Cellular Microtubules, Current Cancer Drug Targets 2015; 15 (1) . https://dx.doi.org/10.2174/1568009615666141215154149
DOI https://dx.doi.org/10.2174/1568009615666141215154149 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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