Identification of TRAIL-inducing compounds highlights small molecule ONC201/TIC10 as a unique anti-cancer agent that activates the TRAIL pathway.
Identification of TRAIL-inducing compounds highlights small molecule ONC201/TIC10 as a unique anti-cancer agent that activates the TRAIL pathway.
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鉴定径流诱导化合物突出了小分子ONC201/TIC10是一种激活步道途径的独特抗癌剂。
DOI：
10.1186/s12943-015-0346-9
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发表时间：
2015-05-01
期刊：
影响因子：
37.3
通讯作者：
El-Deiry WS
中科院分区：
文献类型：
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作者：
Allen JE;Krigsfeld G;Patel L;Mayes PA;Dicker DT;Wu GS;El-Deiry WS
我们之前报道过 ONC201/TIC10 的鉴定，这是一种新型的人 TRAIL 基因小分子诱导剂，可改善重组 TRAIL 的功效限制特性，并且基于其在多个临床前模型中具有良好的安全性和抗肿瘤功效，目前正在晚期癌症中进行临床试验。我们使用 NCI Diversity Set II 进行了高通量荧光素酶报告基因筛选，以鉴定 TRAIL 诱导化合物。小分子介导的 TRAIL 报告活性诱导相对温和，大多数命中化合物诱导低水平的 TRAIL 上调。在候选 TRAIL 诱导化合物中，TIC9 和 ONC201/TIC10 在体外和体内诱导肿瘤细胞持续 TRAIL 上调和凋亡。然而，与 TIC9 不同，ONC201/TIC10 增强了肿瘤细胞死亡，同时保留了正常细胞，并且对正常成纤维细胞缺乏遗传毒性。研究 TRAIL 诱导化合物对细胞信号通路的影响表明，TIC9 和 ONC201/TIC10 是最有效的细胞死亡诱导剂，它们通过灭活 Akt/ERK 专门激活 Foxo3a，从而上调 TRAIL 及其促凋亡死亡受体 DR5。这些研究揭示了 ONC201/TIC10 的选择性活性，使其被选为此类新型抗肿瘤药物的先导化合物，并表明 ONC201/TIC10 通过同时调节 TRAIL 配体及其死亡受体 DR5，成为 TRAIL 途径的独特诱导剂。
We previously reported the identification of ONC201/TIC10, a novel small molecule inducer of the human TRAIL gene that improves efficacy-limiting properties of recombinant TRAIL and is in clinical trials in advanced cancers based on its promising safety and antitumor efficacy in several preclinical models. We performed a high throughput luciferase reporter screen using the NCI Diversity Set II to identify TRAIL-inducing compounds. Small molecule-mediated induction of TRAIL reporter activity was relatively modest and the majority of the hit compounds induced low levels of TRAIL upregulation. Among the candidate TRAIL-inducing compounds, TIC9 and ONC201/TIC10 induced sustained TRAIL upregulation and apoptosis in tumor cells in vitro and in vivo. However, ONC201/TIC10 potentiated tumor cell death while sparing normal cells, unlike TIC9, and lacked genotoxicity in normal fibroblasts. Investigating the effects of TRAIL-inducing compounds on cell signaling pathways revealed that TIC9 and ONC201/TIC10, which are the most potent inducers of cell death, exclusively activate Foxo3a through inactivation of Akt/ERK to upregulate TRAIL and its pro-apoptotic death receptor DR5. These studies reveal the selective activity of ONC201/TIC10 that led to its selection as a lead compound for this novel class of antitumor agents and suggest that ONC201/TIC10 is a unique inducer of the TRAIL pathway through its concomitant regulation of the TRAIL ligand and its death receptor DR5.
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影响因子：
--
作者：
Wagner, Jessica;Kline, Christina Leah;El-Deiry, Wafik S.
通讯作者：
El-Deiry, Wafik S.
影响因子：
3.6
作者：
Kuribayashi, Kageaki;Krigsfeld, Gabriel;El-Deiry, Wafik S.
通讯作者：
El-Deiry, Wafik S.
DOI：
10.1084/jem.190.8.1155
发表时间：
1999-10-18
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Fanger NA;Maliszewski CR;Schooley K;Griffith TS
通讯作者：
Griffith TS
影响因子：
5.3
作者：
Greco, F. Anthony;Bonomi, Philip;Klein, Jerry
通讯作者：
Klein, Jerry
DOI：
10.1073/pnas.0731871100
发表时间：
2003-05-27
影响因子：
11.1
作者：
Ghaffari, S;Jagani, Z;Khosravi-Far, R
通讯作者：
Khosravi-Far, R