The angular structure of ONC201, a TRAIL pathway-inducing compound, determines its potent anti-cancer activity
The angular structure of ONC201, a TRAIL pathway-inducing compound, determines its potent anti-cancer activity
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DOI：
10.18632/oncotarget.2890
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发表时间：
2014-12-30
期刊：
影响因子：
--
通讯作者：
El-Deiry, Wafik S.
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文献类型：
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作者：
Wagner, Jessica;Kline, Christina Leah;El-Deiry, Wafik S.
我们之前从NCI化学文库筛选中发现了TRAIL诱导化合物10(TIC10)，也被称为NSC350625或ONC201，是一种小分子，在临床前癌症模型中具有强大的抗肿瘤效果和良性的安全性。该化学结构最初由Stahle等人发表。艾尔在专利文献中被描述为咪唑并[1，2-a]吡啶并[4，3-d]嘧啶衍生物。NCI和其他机构普遍认为这是正确的结构，这与Allen et在出版物中概述的质谱分析一致。艾尔首次报道了该分子的抗癌特性。最近的一篇文章表明，来自NCI的ONC201材料的化学结构是最初公开的线形[4，3-d]结构的角状[3，4-e]异构体。在这里，我们通过对二盐酸盐形式的核磁共振和X-射线结构分析证实，Ondiceutics生产的ONC201材料是棱角[3，4-e]结构，而不是最初在专利文献和NCI中描述的线形结构。同样，根据我们的生物学评价，先前公开的抗癌活性与角状结构有关，而不是与线形异构体有关。总之，这些研究证实，ONC201由Ondiceutics公司生产或从NCI获得，具有棱角[3，4-e]结构，代表在先前的临床前研究中使用的高活性抗癌化合物，目前正在进入晚期癌症的临床试验。
We previously identified TRAIL-inducing compound 10 (TIC10), also known as NSC350625 or ONC201, from a NCI chemical library screen as a small molecule that has potent anti-tumor efficacy and a benign safety profile in preclinical cancer models. The chemical structure that was originally published by Stahle, et. al. in the patent literature was described as an imidazo[1,2-a]pyrido[4,3-d]pyrimidine derivative. The NCI and others generally accepted this as the correct structure, which was consistent with the mass spectrometry analysis outlined in the publication by Allen et. al. that first reported the molecule's anticancer properties. A recent publication demonstrated that the chemical structure of ONC201 material from the NCI is an angular [3,4-e] isomer of the originally disclosed, linear [4,3-d] structure. Here we confirm by NMR and X-ray structural analysis of the dihydrochloride salt form that the ONC201 material produced by Oncoceutics is the angular [3,4-e] structure and not the linear structure originally depicted in the patent literature and by the NCI. Similarly, in accordance with our biological evaluation, the previously disclosed anticancer activity is associated with the angular structure and not the linear isomer. Together these studies confirm that ONC201, produced by Oncoceutics or obtained from the NCI, possesses an angular [3,4-e] structure that represents the highly active anti-cancer compound utilized in prior preclinical studies and now entering clinical trials in advanced cancers.