Downregulating transcription of the oncogene c-MYC is a feasible strategy for cancer therapy. Stabilization of the G-quadruplex structure present in the c-MYC promoter can suppress c-MYC transcription. Thus, far, several ligands targeting this structure have been developed. However, most have shown no selectivity for the c-MYC G-quadruplex over other G-quadruplexes, leading to uncertain side effects. In this study, through structural modification of aryl-substituted imidazole/carbazole conjugates, a brand-new, four-leaf clover-like ligand called IZCZ-3 was found to preferentially bind and stabilize the c-MYC G-quadruplex. Further intracellular studies indicated that IZCZ-3 provoked cell cycle arrest and apoptosis and thus inhibited cell growth, primarily by blocking c-MYC transcription through specific targeting of the promoter G-quadruplex structure. Notably, IZCZ-3 effectively suppressed tumor growth in a mouse xenograft model. Accordingly, this work provides an encouraging example of a selective small molecule that can target one particular G-quadruplex structure, and the selective ligand might serve as an excellent anticancer agent.

中文翻译：

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发现一种新的四叶三叶草配体作为有效的c-MYC转录抑制剂，特别针对启动子G-四链体

下调癌基因c-MYC的转录是用于癌症治疗的可行策略。c-MYC启动子中存在的G-四链体结构的稳定化可以抑制c-MYC转录。因此，到目前为止，已经开发了靶向该结构的几种配体。然而，大多数没有显示出对c-MYC G-四链体比其他G-四链体的选择性，导致不确定的副作用。在这项研究中，通过芳基取代的咪唑/咔唑共轭物的结构修饰，发现了一种全新的四叶三叶草样配体，称为IZCZ-3，可优先结合并稳定c-MYC G-四链体。进一步的细胞内研究表明IZCZ-3引起细胞周期停滞和凋亡，从而抑制细胞生长，主要是通过特异性靶向启动子G-四链体结构来阻断c-MYC转录。值得注意的是，IZCZ-3在小鼠异种移植模型中有效抑制了肿瘤的生长。因此，这项工作为选择性小分子提供了一个令人鼓舞的例子，该分子可以靶向一个特定的G-四链体结构，并且选择性配体可以用作出色的抗癌剂。