Sudemycins, novel small molecule analogues of FR901464, induce alternative gene splicing.
Sudemycins, novel small molecule analogues of FR901464, induce alternative gene splicing.
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DOI：
10.1021/cb100356k
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发表时间：
2011-06-17
影响因子：
4
通讯作者：
Potter, Philip M.
中科院分区：
文献类型：
--
作者：
Fan, Liying;Lagisetti, Chandraiah;Edwards, Carol C.;Webb, Thomas R.;Potter, Philip M.
两种不相关的细菌天然产物 FR901464 和 pladienolide B 先前已被证明具有显着的体内抗肿瘤活性。这些化合物靶向剪接体的 SF3b 亚基，其中 pladienolide (E7107) 衍生物进入癌症临床试验。然而，由于这些分子的结构复杂性，它们的研究和开发受到了极大的限制。我们通过灵活的对映选择性途径生成了一组新型类似物（Sudemycins），它们具有 FR901464 和 pladienolide 所共有的药效基团，并允许生产克级数量的药物。这些化合物对培养的人肿瘤细胞系表现出细胞毒性，并在异种移植模型中表现出抗肿瘤活性。在这里，我们提出的证据表明，Sudemycins 是人类细胞中内源基因和小基因构建体选择性剪接的有效调节剂。此外，相对于正常细胞，肿瘤细胞中的选择性剪接水平有所增加，并且在动物暴露于药物后，可以在体内的人肿瘤异种移植物中观察到这些修饰。此外，用 Sudemycin 观察到的剪接模式的变化与用 Spliceostatin A 观察到的相似，Spliceostatin A 是一种已知与剪接体的 SF3b 亚基相互作用的分子。因此，我们得出结论，Sudemycins 可以调节选择性剪接 RNA 转录本的产生，并且在药物暴露后，与正常细胞相比，这些改变在肿瘤中更为普遍。这些研究表明，选择性剪接的调节可能在此类药物的抗肿瘤活性中发挥作用。
Two unrelated bacterial natural products, FR901464 and pladienolide B, have previously been shown to have significant anti-tumor activity in vivo. These compounds target the SF3b subunit of the spliceosome, with a derivative of pladienolide (E7107) entering clinical trials for cancer. However, due to the structural complexity of these molecules, their research and development has been significantly constrained. We have generated a set of novel analogues (Sudemycins) that possess the pharmacophore that is common to FR901464 and pladienolide, via a flexible enantioselective route, and allows for the production of gram quantities of drug. These compounds demonstrate cytotoxicity towards human tumor cell lines in culture and exhibit antitumor activity in a xenograft model. Here, we present evidence that Sudemycins are potent modulators of alternative splicing in human cells, both of endogenous genes and from minigene constructs. Furthermore, levels of alternative splicing are increased in tumor cells relative to normal cells and these modifications can be observed in human tumor xenografts in vivo following exposure of animals to the drug. In addition, the change in the splicing pattern observed with the Sudemycins are similar to that observed with Spliceostatin A, a molecule known to interact with the SF3b subunit of the spliceosome. Hence, we conclude that Sudemycins can regulate the production of alternatively spliced RNA transcripts and these alterations are more prevalent in tumor, as compared to normal cells, following drug exposure. These studies suggest that modulation of alternative splicing may play a role in the antitumor activity of this class of agents.
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影响因子：
3.9
作者：
Sumanasekera, Chiranthani;Watt, David S.;Stamm, Stefan
通讯作者：
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影响因子：
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作者：
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影响因子：
7.3
作者：
Lagisetti, Chandraiah;Pourpak, Alan;Webb, Thomas R.
通讯作者：
Webb, Thomas R.