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

• Published in: Journal of medicinal chemistry Vol. 61; no. 6; pp. 2447 - 2459
• Main Authors: Hu, Ming-Hao, Wang, Yu-Qing, Yu, Ze-Yi, Hu, Lu-Ni, Ou, Tian-Miao, Chen, Shuo-Bin, Huang, Zhi-Shu, Tan, Jia-Heng
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 22-03-2018
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.7b01697

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.