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CXI-苯并-84 可逆地结合到秋水仙碱位点的微管蛋白上，并诱导癌细胞凋亡。

CXI-benzo-84 reversibly binds to tubulin at colchicine site and induces apoptosis in cancer cells.

机构信息

Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India.

出版信息

Biochem Pharmacol. 2013 Aug 1;86(3):378-91. doi: 10.1016/j.bcp.2013.05.024. Epub 2013 Jun 6.

DOI:10.1016/j.bcp.2013.05.024
PMID:23747346
Abstract

Here, we have discovered CXI-benzo-84 as a potential anticancer agent from a library of benzimidazole derivatives using cell based screening strategy. CXI-benzo-84 inhibited cell cycle progression in metaphase stage of mitosis and accumulated spindle assembly checkpoint proteins Mad2 and BubR1 on kinetochores, which subsequently activated apoptotic cell death in cancer cells. CXI-benzo-84 depolymerized both interphase and mitotic microtubules, perturbed EB1 binding to microtubules and inhibited the assembly and GTPase activity of tubulin in vitro. CXI-benzo-84 bound to tubulin at a single binding site with a dissociation constant of 1.2±0.2μM. Competition experiments and molecular docking suggested that CXI-benzo-84 binds to tubulin at the colchicine-site. Further, computational analysis provided a significant insight on the binding site of CXI-benzo-84 on tubulin. In addition to its potential use in cancer chemotherapy, CXI-benzo-84 may also be useful to screen colchicine-site agents and to understand the colchicine binding site on tubulin.

摘要

在这里，我们从苯并咪唑衍生物库中使用基于细胞的筛选策略发现 CXI-苯并-84 是一种有潜力的抗癌剂。CXI-苯并-84 抑制有丝分裂中期的细胞周期进展，并在着丝粒上积累纺锤体组装检查点蛋白 Mad2 和 BubR1，随后在癌细胞中激活凋亡性细胞死亡。CXI-苯并-84 使间期和有丝分裂微管解聚，破坏 EB1 与微管的结合，并抑制体外微管蛋白的组装和 GTP 酶活性。CXI-苯并-84 与微管蛋白在单一结合位点结合，解离常数为 1.2±0.2μM。竞争实验和分子对接表明，CXI-苯并-84 结合到秋水仙碱结合位点上的微管蛋白。此外，计算分析提供了关于 CXI-苯并-84 结合到微管蛋白上的结合位点的重要见解。除了在癌症化疗中的潜在用途外，CXI-苯并-84 也可能有助于筛选秋水仙碱结合位点的试剂，并了解微管蛋白上的秋水仙碱结合位点。

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