Discovery of a New Four-Leaf Clover-Like Ligand as a Potent c-MYC Transcription Inhibitor Specifically Targeting the Promoter G-Quadruplex

作者：Ming-Hao Hu, Yuqing Wang, Ze-Yi Yu, Luni Hu, Tian‐Miao Ou, Shuo-Bin Chen, Zhi‐Shu Huang, Jia‐Heng Tan · 发表于：Journal of Medicinal Chemistry · 年份：2018 · DOI：10.1021/acs.jmedchem.7b01697 · 被引用次数：98 · 研究领域：DNA and Nucleic Acid Chemistry、Advanced biosensing and bioanalysis techniques、RNA Interference and Gene Delivery

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.