G-quadruplexes are unique four-stranded structures formed by guanine-rich nucleic acid sequences. G-quadruplexes are widely distributed in many important regulatory regions in the human genome, notably in telomeres and promoters of oncogenes, such as c-MYC, c-KIT, BCL-2, and KRAS. G-quadruplex structures play a significant regulatory role in many biological processes, such as DNA replication, transcription, and genome stability. Downregulating transcription of the oncogene c-MYC is a feasible strategy for cancer therapy. Selective small molecule that can target one particular G-quadruplex structure, and the selective ligand might serve as an excellent anticancer agent.

Ming-Hao Hu, et al found that IZCZ-3 inhibited c-MYC transcription by binding and stabilizing the promoter G-quadruplex in cells. Especially, IZCZ-3 significantly inhibits cancer cell proliferation by inducing cell cycle arrest at G0/G1 and apoptosis. IZCZ-3 has a significant cytotoxic effect on the cancer cells, suggesting that IZCZ-3 is more effective against cancer cells than against c-MYC-independent normal cells. Moreover, IZCZ-3 specifically downregulates c-MYC transcription in cancer cells. IZCZ-3 specifically targets the G-quadruplex structure in the c-MYC oncogene promoter and hence downregulated its transcription. In vivo, IZCZ-3 inhibits tumor growth in a human cervical squamous cancer xenograft. IZCZ-3 also exhibits good antitumor ability by inhibiting cervical squamous cancer growth in nude mice. Collectively, these data reveal that IZCZ-3 binds to the c-MYC G-quadruplex with a much stronger affinity than to the other G-quadruplexes.

All in all, through downregulating c-MYC expression, IZCZ-3 disturbs the functions of cell cycle and apoptosis regulators, thereby inducing G0/G1 arrest and apoptosis.

Hu MH, et al. Discovery of a New Four-Leaf Clover-Like Ligand as a Potent c-MYC Transcription Inhibitor Specifically Targeting the Promoter G-Quadruplex. J Med Chem. 2018 Mar 22;61(6):2447-2459.